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DUPILUMAB BECOMES FIRST BIOLOGIC APPROVED FOR COPD

lungs floating in doctor's hands
Dupilumab (Dupixent®), a monoclonal antibody that inhibits interleukin-4 (IL-4) and 13 (IL-13), recently became the first biologic approved to treat COPD. Dupilumab also has indications for asthma, atopic dermatitis, nasal polyposis, eosinophilic esophagitis, and prurigo nodularis. The COPD indication was based on two studies that found dupilumab reduced exacerbations and improved lung function, compared to placebo, in COPD patients with evidence of type 2 inflammation (defined as a blood eosinophil count ≥ 300 cells/mcl). In the BOREAS study (N=939), the annualized rate of moderate or severe COPD exacerbations was lower with dupilumab (0.78 vs 1.10, p<0.001), and the pre-bronchodilator FEV1 increased more with dupilumab at 52 weeks (+153 ml vs +70 ml, p<0.001). Similar results were observed in the NOTUS study (N=935), which also showed lower exacerbation rates (0.86 vs 1.30) and improved FEV1 (+139 vs +82) with dupilumab. [NOTUS abstract] Dosing in both studies was 300 mg every two weeks, and adverse events were similar to placebo.

Dupilumab, already a blockbuster drug for Regeneron and Sanofi, is now approved for COPD patients with an eosinophilic phenotype, typically defined as a blood eosinophil count consistently above 300 cells/mcl. For context, the average eosinophil count in the general adult population is 100 to 150 cells/mcl, and most labs consider a normal range to be 0 to 500 cells/mcl. Dupilumab is expensive but covered by most Medicare Part D plans, which may help many COPD patients access it.
Placebos are real medicine
placebo pill
Placebos work, even when patients know they are getting one. A recent study randomized 101 adults with chronic back pain to an open-label subcutaneous injection of saline or usual care. The injection group was told their treatment was a placebo with no active ingredient. After one month, pain intensity was significantly lower in the injection group. At one year, there was no difference in pain; however, depression, anger, anxiety, and sleep disruption were significantly better in the injection group. Every day, providers prescribe or administer countless therapies with no proven benefit, which may not matter since the idea that something was done is all many people need.

NEW H. PYLORI TREATMENT GUIDELINES

picture of h. pylori bacteria
The American College of Gastroenterology (ACG) released updated treatment guidelines for Helicobacter pylori (H. pylori), a gram-negative bacteria that infects the stomach and raises the risk of peptic ulcers and gastric cancer. In some parts of the world, H. pylori is prevalent in more than 50% of the population, while in the U.S., about 26% of people are infected. The new guidelines differ from those released in 2017 in that regimens with a PPI and clarithromycin (e.g., Prevpac) are no longer preferred due to clarithromycin resistance that has lowered their efficacy to less than 70%. The guidelines also recommend two regimens with vonoprazan, a new acid-reducing drug that works by competing with potassium ions at proton pumps instead of covalently binding them like PPIs. Recommended first-line therapies are listed below.
  • Optimized bismuth quadruple therapy: PPI + bismuth subsalicylate or subcitrate + metronidazole + tetracycline; cost - $60; cure rate - 87%
  • Rifabutin triple therapy: omeprazole + amoxicillin + rifabutin; cost - $150 (prescribed separately) or $800 (Talicia); cure rate - 84%
  • Voquezna DualPak: vonoprazan + amoxicillin; cost - $660 (prescribed separately) or $830 (DualPak); cure rate - 79%
  • Voquezna TriplePak: vonoprazan + clarithromycin + amoxicillin; cost - $690 (prescribed separately) or $830 (TriplePak); cure rate - 81%

The urea breath test and fecal antigen test are recommended for diagnosis because they detect active disease, whereas the serologic antibody test is nonspecific. A test for cure, using the same method performed for diagnosis, is recommended in all patients 30 or more days after treatment completion. Patients who are still positive should be treated with a salvage regimen with the choice based on prior therapy received and sensitivity testing if available. The recurrence rate in the U.S. after successful treatment is 1% per year. Regimen details for treatment-naive and treatment-experienced patients are available at the link below.
Finerenone beneficial in heart failure with preserved ejection fraction
Finerenone (Kerendia®), a nonsteroidal mineralocorticoid receptor antagonist (MRA) approved for diabetic kidney disease, was recently evaluated in heart failure with preserved ejection fraction (HFpEF). The FINEARTS-HF trial randomized 7463 patients with symptomatic heart failure and an EF of 40% or more to finerenone 20 - 40 mg/day or placebo. After a median of 32 months, the primary outcome, a composite of heart failure events and death from CVD causes, was lower in the finerenone group (14.9%/year vs 17.7%/year, p=0.007). There was no significant difference in overall mortality (16.4% vs 17.4%), while hyperkalemia (14.3% vs 6.9%) and hypotension (18.5% vs 12.4%) were more common in finerenone-treated patients.

Finerenone blocks aldosterone receptors in the renal collecting duct, similar to spironolactone and eplerenone. Spironolactone was studied in patients with HFpEF in the TOMCAT study (N=3445), where it reduced heart failure hospitalizations (12% vs 14.2%, p=0.04) but did not achieve significance for the primary outcome, a composite of CVD events (18.6% vs 20.4%, p=0.14). However, a post-hoc analysis that excluded data from Russia and Georgia, where events were unusually low, found a significant benefit for the primary outcome.

The ACC 2023 HFpEF guidelines recommend spironolactone or eplerenone in most patients with volume overload. Finerenone appears to provide a similar benefit with the drawback of no generic and higher cost. Regardless of the MRA used, patients should be monitored closely for hyperkalemia and hypotension.

STUDY CONFIRMS ANTIPLATELET AGENTS SHOULD NOT BE COMBINED WITH ANTICOAGULANTS IN STABLE CAD AND AF

pills with stethascope
Patients with atrial fibrillation (AF) and coronary artery disease (CAD) have indications for both an anticoagulant and an antiplatelet agent. Past guidance on managing these patients was indecisive. In 2019, the AFIRE study was published, which found that anticoagulant monotherapy was equally effective and safer than dual therapy (anticoagulant + antiplatelet). A second study addressing this issue was recently published. In the EPIC-CAD study, 1040 patients with AF and stable CAD were randomized to edoxaban monotherapy or dual therapy (edoxaban + aspirin or P2Y12 inhibitor). After 12 months, major ischemic events were similar between groups (edoxaban 1.6%, dual therapy 1.8%), while major bleeding or clinically relevant nonmajor bleeding was higher with dual therapy (4.7% vs 14.2%).

After AFIRE was published, AHA guidelines recommended anticoagulant monotherapy in AF with stable CAD, and EPIC-CAD supports this guidance.

I still encounter patients who are taking aspirin with anticoagulants. Since aspirin is not prescribed, providers sometimes forget to ask about it. Likewise, patients forget to report it. When initiating anticoagulants, it is important to take a moment and discuss antiplatelet agents with patients, including OTC NSAIDs like ibuprofen and naproxen. Conditions where dual therapy may still be recommended include AF with recent cardiac stent placement and a subgroup of patients with mechanical heart valves.

New COPD drug approved
Ensifentrine (Ohtuvayre®), a phosphodiesterase 3 and 4 inhibitor (PDE3/4), was recently approved to treat COPD. PDE inhibitors increase pulmonary levels of cAMP, an intracellular signaling molecule that stimulates bronchodilation. In a 24-week trial enrolling 790 moderate-to-severe COPD patients, ensifentrine 3 mg twice daily via nebulizer increased the average post-dose FEV1 over 12 hours by 94 ml compared to placebo. Moderate or severe COPD exacerbations were also lower with ensifentrine (0.24/year vs 0.42/year ); however, daily rescue inhaler use was not significantly different between groups. Ensifentrine side effects were mild and similar to placebo.

Ensifentrine is the second PDE inhibitor approved for COPD. Roflumilast (Daliresp®), which only inhibits PDE4, has been available since 2011. It is an oral tablet and has significant GI effects, including weight loss, nausea, and diarrhea, which have limited its uptake. The 2023 GOLD COPD guidelines list roflumilast as a fourth- or fifth-line agent in patients with severe COPD.

NEWS IN BRIEF

Steroid tapering recommendations

prednisone box
One of the first bits of medical knowledge all providers learn in training is that glucocorticoids should be tapered to prevent hypothalamic-pituitary-adrenal (HPA) axis suppression. Despite this universal rule, little professional guidance has been published, causing tapering practices to vary widely among clinicians. Finally, this past June, the Endocrine Society, in conjunction with the European Society of Endocrinology, published steroid-tapering recommendations that provide meaningful guidance. Links to the recommendations and our summary are provided below.

Atopic dermatitis (AD) recommendations

atopic dermatitis on elbow
The treatment of atopic dermatitis (AD) has traditionally been straightforward, with topical steroids and calcineurin inhibitors being the primary options. In recent years, new therapies, including Janus kinase (JAK) inhibitors, biologics, and phosphodiesterase-4 (PDE-4) inhibitors, have been approved, expanding treatment options. The American Academy of Allergy, Asthma & Immunology (AAAAI) recently published guidelines for AD treatment, and we have consolidated them into easy-to-follow steps available at the link below.

PCOS recommendations

uterus and ovary illustration
Most providers don't want to read an encyclopedia on polycystic ovary syndrome (PCOS), but concise and up-to-date diagnostic criteria and treatment recommendations can come in handy, so we added straightforward PCOS algorithms to our female hormone physiology page.

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.

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.

POPULAR PAGES

CHARTS

BASICS

MEDICATIONS

NEW DRUGS

POPULAR BUT UNPROVEN

  • 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?
Blood test approved for colon cancer screening
picture of Shield box
The Shield test, a blood assay that detects alternations associated with colorectal cancer (CRC) in cell-free DNA, was recently approved to screen for colon cancer in average-risk individuals. In a study of 10,258 adults using colonoscopy as the reference standard, Shield had the following accuracy:
  • Sensitivity (any colorectal cancer): 83.1%
  • Sensitivity (stage 1 colorectal cancer): 54.5%
  • Sensitivity (advanced adenoma✝): 13.2%
  • Specificity (colorectal cancer or advanced adenoma): 89.6%
  • ✝Advanced adenomas are polyps with precancerous features

Shield is actually the second blood test approved for colon cancer screening. The Epi proColon test, which detects a bloodborne marker of CRC called methylated SEPT9 DNA, was approved in 2016. It has a sensitivity of 69% for any CRC and 41% for stage 1 CRC. For comparison, Cologuard, the widely advertised stool DNA test, has sensitivities of 92% and 88%, respectively.

When it comes to DNA-based colon cancer screening, Cologuard is the clear winner; however, none of the assays are particularly good at detecting precancerous adenomas (Shield - 13.2%, Epi proColon - 21.5%, Cologuard - 42%). As far as cost, Shield runs $895, Epi proColon $192, and Cologuard $500. Professional guidelines recommend repeating Cologuard every three years. Epi proColon has never been incorporated into any guidelines, and Shield is too new to have been considered.
Paxlovid does not prevent COVID in exposed patients
Paxlovid box
Some patients and providers assume Paxlovid helps to prevent COVID in exposed patients, and it is often prescribed for this purpose. To evaluate this use, researchers randomized 2736 asymptomatic adults who had been exposed to a household contact with COVID within 96 hours to Paxlovid for 5 or 10 days or matching placebo. Other inclusion criteria included no known history of COVID and a negative baseline COVID antigen test. Only 13% of participants had received one or more COVID vaccines, and 73% had at least one risk factor for severe COVID. At the end of the trial, the primary outcome, symptomatic COVID confirmed by PCR or antigen testing through 14 days, occurred in 2.6% of the Paxlovid 5-day group, 2.4% of the 10-day group, and 3.9% of the placebo group. All Paxlovid-placebo comparisons were nonsignificant.

This is the second negative Paxlovid study Pfizer has funded. A study published in April found that Paxlovid did not shorten the time to symptom resolution, compared to placebo, in a mix of vaccinated and unvaccinated adults with new-onset COVID. For COVID protection, vaccination continues to be the clear winner.

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.