Arrow pointing up

FEATURED

VITAMIN K2 RELIEVES NOCTURNAL LEG CRAMPS IN SMALL STUDY

woman with leg cramps
Nocturnal leg cramps are a common complaint, affecting 50% to 60% of adults at some point during their lifetime. When asked about treatment, providers struggle to provide meaningful advice, as there are no FDA-approved therapies, and traditional remedies like quinine have potentially serious adverse events, including arrhythmias and sensory disturbances (e.g., tinnitus). Given the lack of options, there has been interest in using a form of vitamin K that may have anti-spasmodic properties.

Vitamin K exists in two primary forms:
  • Vitamin K1 (phylloquinone): Most common form; found in plants, especially green leafy vegetables; essential for blood clotting
  • Vitamin K2 (menaquinone): Present in some animal products and fermented foods; has ten subtypes, designated menaquinone-4 through menaquinone-13, based on the length of the side chain; plays a role in blood clotting and calcium regulation

Menaquinone-7, a subtype of vitamin K2, is believed to inhibit calcium uptake by muscle cells, thereby preventing excessive contraction and potentially alleviating nocturnal leg cramps. To test this theory, researchers randomized 199 adults aged 65 and older with nocturnal leg cramps (baseline average 2.65 cramps/week) to menaquinone-7 180 mcg at bedtime or placebo. At the end of the study, the average number of weekly leg cramps in the menaquinone-7 group decreased to 0.96, while the placebo group saw an increase to 3.6 (p<0.001). No adverse events were reported in either group.

Even though this study was small, it provides useful information, as there is a lack of evidence-based therapies for leg cramps. Menaquinone-7 (also called MK-7 or menaquinone for short) is available on Amazon from numerous manufacturers in doses of 100 and 200 mcg. In the future, I will suggest that patients with bothersome cramps give it a try. The only apparent major precaution is its potential to interfere with vitamin K antagonists, precluding its use in patients on warfarin.
Left atrial appendage closure bests anticoagulation after ablation for atrial fibrillation
illustration of the heart
Catheter ablation for atrial fibrillation (AF) is not typically curative, requiring patients to continue anticoagulants after the procedure. Left atrial appendage (LAA) closure has demonstrated similar efficacy to anticoagulation in preventing AF-induced strokes. A recent study randomized patients who were receiving ablation for AF to LAA closure (Watchman device) or continued anticoagulation. After 36 months, CVD outcomes, including stroke, were similar between groups (LAA closure 5.3%, anticoagulation 5.8%); however, major bleeding events were significantly higher in the anticoagulant group (8.5% vs 18.1%). This study makes a strong case for concomitant LAA device closure during ablation, particularly in patients who wish to discontinue anticoagulation or have significant bleeding risk.

EYE-OPENING STUDY LOOKS AT PREVALENCE OF SECONDARY HYPERTENSION

doctor checking blood pressure
Secondary hypertension is high blood pressure with an identifiable and sometimes treatable cause. Studies have suggested that secondary hypertension may be present in 10% of individuals with hypertension and up to 30% of those with resistant hypertension. Despite its significant prevalence, many providers do not consider secondary causes when diagnosing hypertension, as obesity and essential hypertension, which affects up to 50% of U.S. adults, are so common that other etiologies are overlooked. To further explore the issue, researchers performed a cross-sectional study involving 2090 hypertensive adults aged 18 to 40 who underwent comprehensive evaluations for secondary causes. Secondary hypertension was identified in 29.6% of participants (N=619), with the most frequent etiologies being:
  • Primary aldosteronism (54.8%)
  • Primary kidney disease (12.9%)
  • Drugs or substances (6%)
  • Pheochromocytoma/functional paraganglioma (5.9%)
  • Other (2.7%)
Factors associated with a higher prevalence of secondary causes included female sex, hypokalemia, treatment with at least two medications, no family history of hypertension, BMI less than 25, and diabetes.

This study was eye-opening, as I rarely consider secondary hypertension in adult patients. So many people are overweight and/or out of shape, it is easy to fall into the trap of attributing most conditions to these issues. After seeing these results, I will be more inclined to consider secondary causes, particularly in patients with factors associated with greater risk.
Wegovy (semaglutide) improves knee osteoarthritis in study
Obese woman with knee pain
Knee osteoarthritis (OA) is caused and worsened by obesity, as both mechanical stress and obesity-induced inflammation accelerate joint destruction. Weight loss improves knee OA, with studies showing a 2% improvement in the WOMAC pain, function, and stiffness scores for every 1% reduction in body weight. To evaluate the effects of Wegovy-induced weight loss on knee OA (based on clinical and X-ray findings), researchers randomized 407 patients (82% female | average age 56) with a BMI of 30 or greater and moderate knee OA to Wegovy (target dose 2.4 mg/week) or placebo. The primary outcomes were percent change in body weight and change in the WOMAC pain score (scale 0 - 100, with higher scores meaning worse outcomes) at week 68. At baseline, the average BMI was 40.3 and the average WOMAC score was 70.9. After 68 weeks, the percent decrease in body weight was 13.7% in the Wegovy group and 3.2% in the placebo group (p<0.001). Reductions in the WOMAC pain score were superior with Wegovy (41.7 vs 27.5, p<0.001), as were measures of knee function. Drug discontinuations due to adverse events were slightly higher in Wegovy-treated patients (6.7% vs 3%) [Full trial summary].

As expected, Wegovy-induced weight loss improved knee pain and function in a predominantly female population (82%) with moderate knee OA. A missed opportunity in the study was the absence of follow-up imaging to assess for changes in joint pathology.

Wegovy and Zepbound continue to rack up positive studies, as the health benefits of significant weight loss are profound. Other obesity-related conditions improved by GLP therapies include heart failure with preserved ejection fraction, cardiovascular disease, nonalcoholic steatohepatitis, and obstructive sleep apnea.

STUDY COMPARES HIP REPLACEMENT SURGERY TO PHYSICAL THERAPY IN SEVERE OA

illustration of implanted hip prosthesis
Hip replacement surgery is the routine treatment for severe hip osteoarthritis (OA), with over 450,000 procedures performed annually in the U.S. alone. Despite its popularity, randomized trials evaluating its effectiveness are lacking. To help close the knowledge gap, researchers in Denmark randomized 109 patients 50 and older (mean age 67.6 years) with severe hip OA to total hip replacement surgery or physical therapy (PT) that included resistance training. The primary outcome was the change in the Oxford Hip Score (scale 0 to 48 with higher scores indicating less pain and better function) at 6 months; the baseline score in both groups was 25. At study conclusion, increases in the Oxford score were significantly greater in the surgery group compared to the PT group (15.9 points vs 4.5 points, p<0.001). At 6 months, 9% of patients assigned to surgery had not received it, while 21% assigned to PT had undergone hip replacement (crossovers). Despite the significant number of crossovers in the PT group, surgery was still superior in the intention-to-treat analysis.

The main weakness of the study is the lack of blinding, which would have required a sham procedure in the control group. However, simulating hip replacement surgery would be difficult given the complexities and aftercare of such a major procedure, making a sham control impractical. While entirely objective evidence does not exist, most patients experience profound pain relief and improvement in mobility after joint replacement surgery, suggesting these procedures are highly effective.

Learn more about the effects of sham procedures and crossovers on study outcomes by taking our CME course, Medical Study Analysis.
Orlynvah, a new oral antibiotic for female UTI
woman with urinary tract infection
Orlynvah, a combination of sulopenem and probenecid, was recently approved to treat uncomplicated female UTIs. Sulopenem is a beta-lactam antibiotic in the penem class that inhibits bacterial cell wall synthesis. Probenecid inhibits renal organic anion transporter 3 (OAT3), reducing sulopenem clearance and increasing its exposure. Orlynvah was compared to ciprofloxacin (250 mg BID for 3 days) in 1671 women with acute uncomplicated UTI. The primary endpoint - resolution of UTI symptoms and a urine culture showing less than 103 CFU/mL of the culprit bacteria at day 12 - occurred in 65.6% of the sulopenem group and 67.9% of the ciprofloxacin group (diff -2.3%, 95%CI [-7.9 to 3.3]). In the subgroup of patients with ciprofloxacin-resistant bacteria, cure rates were 62.6% and 36%, respectively (p<0.001). [PubMed abstract]

Orlynvah is dosed as one tablet with food twice daily for 5 days. Common side effects include diarrhea (10%) and nausea (4%). Drug interactions, which are related to probenecid's OAT1/3 inhibition, include ketorolac, ketoprofen, indomethacin, naproxen, methotrexate, rifampin, lorazepam, and sulfonylureas.

Orlynvah is considerably more expensive than available therapies, creating issues with insurance coverage and affordability that likely limit its use to cases of multidrug-resistant bacteria. However, sulopenem is not a part of standard urine culture sensitivity reports. Imipenem, a carbapenem related to sulopenem, is often included and may be used as a surrogate marker of sulopenem sensitivity, with the understanding that cross-sensitivity between the drugs has not been validated in a study.

Orlynvah is the second new drug approved for UTIs in 2024. Pivmecillinam (Pivya), a penicillin antibiotic, was approved in April; however, it was discontinued by the manufacturer shortly after its approval for reasons that are unclear.

NEWS IN BRIEF

AGA publishes vonoprazan recommendations

illustration of the stomach
The American Gastroenterological Association (AGA) recently published recommendations for the use of vonoprazan (Voquezna), a novel acid-reducing drug. Vonoprazan inhibits acid production by competing with potassium ions at gastric H+/K+-ATPase proton pumps; this differs from traditional proton pump inhibitors (PPIs), which inhibit the pump through covalent binding. Like most new drugs, vonoprazan is expensive and not covered by many insurance plans. The AGA guidelines do not recommend vonoprazan as a first-line agent for GERD, erosive esophagitis, or peptic ulcers. However, they do endorse its use for H. pylori because vonoprazan-containing regimens have demonstrated higher cure rates than those with PPIs.

Derm group publishes recommendations for oral minoxidil in hair loss treatment

man with androgenic alopecia
Low-dose oral minoxidil (LDOM) has become a popular treatment for hair loss. Small studies have shown it to be effective, but up until now, no consensus professional guidance has been published. Recently, a group of 43 dermatologists specializing in hair loss treatment issued a statement on LDOM that provides guidance on patient selection, therapy management, contraindications, precautions, and dosing. Links to a summary of the guidelines and a recent study comparing oral and topical minoxidil for male androgenic alopecia are provided below.

CDC recommends all people 50 and older get pneumococcal vaccine

CDC logo
The Centers for Disease Control and Prevention (CDC) recently lowered the recommended age for the pneumococcal vaccine in average-risk individuals. The new guidance recommends that all people 50 and older receive one dose of PCV15 (Vaxneuvance), PCV20 (Prevnar 20), or PCV21 (Capvaxive). If PCV15 is used, a dose of PPSV23 (Pneumovax) is recommended a year later. The recommendation is based on presumed benefits and surrogate endpoints (antibody titers), rather than clinical outcomes like hospitalizations and mortality. Only one large study (N=84,496) has ever evaluated the effects of universal pneumonia vaccination on clinical outcomes. It found no effect of PCV13 on community-acquired pneumonia or overall mortality. Smaller studies evaluating PPSV23 in high-risk populations have also been disappointing.

New AHA perioperative cardiac management recommendations

patient receiving ecg
The American Heart Association (AHA) recently published updated guidelines for preoperative cardiac evaluation in patients undergoing noncardiac surgery. We condensed the recommendations into a simple algorithm available at the link below. The guidelines also include new recommendations for periprocedural antithrombotic management, including two illustrations that clearly convey when to stop and start direct-acting oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) based on procedure bleeding risk. Recommendations regarding antiplatelet therapy, including patients with recent PCI, are also provided. Links to all the above-mentioned information are available below.

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?
Next generation Cologuard test approved
Cologuard Plus logo
The FDA recently approved Cologuard Plus, the next generation of the Cologuard fecal DNA test used to screen for colon cancer. Cologuard Plus includes a new molecular panel intended to improve the test's specificity (i.e., fewer false positives). Like the original Cologuard test, a fecal immunochemical test (FIT) is performed with the DNA assay. If either test is positive, results are deemed positive without details on the individual tests. Cologuard Plus was evaluated in the BLUE-C cohort study, where 20,176 participants 40 years and older (average age 63 years) took the test before undergoing screening colonoscopy. The original Cologuard test was evaluated in a similar study published in 2014. A comparison of how the two tests performed is presented in the table below.

Measure Cologuard Cologuard Plus
Colorectal cancer
(Sensitivity)		 92.3% 93.9%
Colorectal cancer
(Specificity)		 89.8% 92.7%
Precancerous lesion
(Sensitivity)		 42.4% 43.4%
While the absolute difference in specificity may seem small (2.9%), when applied to a large screening population, the improvement is meaningful. Consider the following: Since its launch in 2014, over 16 million Cologuard tests have been processed. Assuming 2 million tests are performed annually on a population with a colorectal cancer prevalence of 0.3%, an improvement in specificity of 2.9% equates to 57,826 fewer false positives (and follow-up colonoscopies) per year. On the sensitivity side, a 1.6% improvement means 96 fewer cancer cases will be missed. Presumably, the manufacturer, Exact Sciences, will now phase out Cologuard and replace it with Cologuard Plus.
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.

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.