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CLOPIDOGREL BESTS ASPIRIN IN CHRONIC CORONARY DISEASE (CCD)

Low-dose aspirin is currently recommended as monotherapy to reduce atherosclerotic events in patients with chronic coronary disease (CCD). To explore the effects of other antiplatelet agents, researchers in South Korea performed SMART-CHOICE 3, a randomized, open-label study that compared clopidogrel 75 mg daily to aspirin 100 mg daily in 5506 high-risk CCD patients who had completed standard dual antiplatelet therapy after PCI. Over a median follow-up of 2.3 years, the primary outcome, a composite of death from any cause, myocardial infarction, or stroke, occurred in 4.4% of the clopidogrel group and 6.6% of the aspirin group (hazard ratio 0.71 [95% CI 0.54-0.93]; p=0.013). There was no significant difference in bleeding risk.

These findings align with a previous 2021 study, HOST-EXAM (N=5438), which similarly found clopidogrel monotherapy superior to aspirin for preventing a composite of CVD events in South Korean patients (5.7% vs 7.7%, p=0.003). Despite these results favoring clopidogrel, the 2023 AHA CCD guidelines, published after HOST-EXAM but before SMART-CHOICE 3, still recommend aspirin as first-line therapy. The authors cite weaknesses in HOST-EXAM, including its open-label design, homogenous South Korean population (high CYP2C19 loss-of-function allele prevalence), and low event rate, as reasons for sticking with aspirin. Until updated guidelines are published, it is unclear if SMART-CHOICE 3 will change this position.

ACP issues acute migraine treatment recommendations

The American College of Physicians (ACP) recently published recommendations for the acute treatment of episodic migraine headache in nonpregnant adults. The guidance recommends NSAIDs and/or acetaminophen as first-line therapy, with the addition of a triptan in nonresponders. Third-line therapy includes CGRP receptor antagonists (rimegepant, ubrogepant, or zavegepant) or dihydroergotamine. Lastly, lasmiditan may be used. Patients who do not respond to an NSAID or triptan may benefit from switching to another drug within the same class. The recommendations do not favor specific drugs within each class. Opioids and butalbital are not recommended, and patients should be made aware of medication overuse headache syndrome, a condition where headaches, occurring on 15 or more days a month, are regularly treated with medications. Lifestyle therapies, including good hydration, exercise, sufficient sleep, and regular meals, are also recommended.

STUDY FINDS RYBELSUS LOWERS CARDIOVASCULAR EVENTS IN TYPE 2 DIABETES

Semaglutide, a GLP-1 analog, is available in two injectable forms (Wegovy and Ozempic) and an oral tablet (Rybelsus). Wegovy and Ozempic have been proven to reduce cardiovascular events in trials, leading to FDA-approved indications for cardiovascular disease (CVD) reduction in obesity and diabetes, respectively. The effects of Rybelsus on cardiovascular events were evaluated in the 2019 PIONEER-6 Trial (N=3183), where the absolute risk of a composite CVD outcome over 16 months was 3.8% with Rybelsus and 4.8% with placebo, a 1% difference that was noninferior to placebo (p<0.001) but not superior (p=0.17). Hoping to achieve a trifecta, Novo Nordisk funded another Rybelsus trial (SOUL Study) that enrolled 9650 diabetics with an A1C between 6.5% and 10% and a history of CVD or eGFR < 60 ml/min. Participants were randomized to Rybelsus with a target dose of 14 mg/day or placebo. After 48 months, a composite of CVD events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) was lower in the Rybelsus group than the placebo group (12% vs 13.8%, p=0.006). HgA1c reduction at Week 104 was 0.71% in the Rybelsus group and 0.15% with placebo, while weight loss was 9.3 lbs and 2.8 lbs, respectively.

After missing statistical significance in the PIONEER-6 study, Novo Nordisk performed the larger and longer SOUL study, where Rybelsus was found to be superior to placebo for a composite of CVD events. Larger sample sizes and longer study durations, leading to more outcome events, help to narrow confidence intervals and increase the chance of a significant result (to learn more about these concepts, take our Medical Study Analysis CME). An analysis adjusting for changes in HgA1c and weight would be informative to see if Rybelsus has a benefit independent of its glucose-lowering and weight-loss effects.

Male-partner treatment decreases bacterial vaginosis recurrence

Bacterial vaginosis (BV), affecting up to 30% of young women, has a high recurrence rate, with over 50% of women experiencing reinfection within 12 weeks. The cause of BV is poorly understood, but women who report sex with a regular partner have twice the risk of those who are not sexually active. This observation has led to speculation that the condition is sexually transmitted. However, previous studies where females and their male partners were treated with oral therapy have not demonstrated a reduction in recurrence. One possible explanation for these findings is that oral therapies alone may not be sufficient to clear cutaneous penile carriage of bacterial vaginosis–associated organisms. To test this theory, Australian researchers randomized monogamous couples in which the woman had BV to female-only treatment (female-only group) or female and male partner treatment (partner-treatment group). In both groups, females received metronidazole 400 mg twice daily for 7 days or intravaginal metronidazole or clindamycin if contraindicated. In the partner-treatment group, males received the same metronidazole regimen along with 2% clindamycin cream applied to the penile skin twice daily for 7 days. During follow-up, females were tested for BV at day 8, week 4, week 8, week 12, and as needed for symptoms. At study conclusion, the primary outcome, BV recurrence within 12 weeks, was significantly lower in the partner-treatment group compared to the female-only group (35% vs 63%, p<0.001)

This study provides some insight into BV and sexual transmission. It also raises the question of whether topical therapy alone in male partners, including over-the-counter creams like Neosporin, could reduce recurrence. Lastly, it's important to note that 35% of women in the partner-treatment group had a recurrence, suggesting that some type of underlying predisposition plays a significant role in BV susceptibility.

ACP PUBLISHES MIGRAINE PREVENTION GUIDELINES

The American College of Physicians (ACP) recently published migraine prevention guidelines. The recommendations are based on a systematic review and network meta-analysis that they performed and are intended for nonpregnant adults with episodic migraine (defined as 1 to 14 headache days per month). Key recommendations include:

First-line therapies: Beta-blocker (metoprolol or propranolol), valproate, venlafaxine, amitriptyline
Second-line therapies: CGRP receptor antagonists (atogepant, rimegepant) or CGRP antibodies (eptinezumab, erenumab, fremanezumab, or galcanezumab)
Third-line therapy: Topiramate

All of the guidelines are based on low-certainty evidence, as there are few meaningful head-to-head trials comparing migraine drugs. Their reasoning for recommending CGRP drugs over topiramate is that topiramate has a less favorable side effect profile.

Migraine prevention has always been the Wild West of pharmacotherapy, as a broad range of medications with seemingly unrelated mechanisms are used for treatment. Fortunately, most recommended drugs are affordable. The newer CGRP drugs are expensive and have modest efficacy in trials, reducing average migraine days per month by 1 - 2 compared to placebo. Notably, placebo typically performs well in migraine trials, likely reflecting overdiagnosis, as patients and some providers tend to label all headache syndromes as migraines.

Expert group recommends against popular procedures for chronic spine pain

Spinal injections, frequently performed in pain medicine practices, are a common intervention for chronic back pain, with an estimated 9 to 11 million injections performed annually in the US alone. Despite their widespread use, studies examining their efficacy have been mixed, with placebo-controlled trials typically finding no effect. [PMID 21914755, PMID 24988555] To further explore the issue, the British Medical Journal convened a panel comprising four patients with chronic spine pain, 10 clinicians experienced in managing chronic spine pain, and eight methodologists. The group reviewed randomized controlled trials and observational studies involving spine procedures and issued the following recommendations:

The following procedures have no proven benefit and should not be offered for radicular or axial spine pain in the cervical or lumbar region:

Epidural injection of local anesthetic, steroids, or their combination
Joint radiofrequency ablation with or without joint targeted injection of local anesthetic plus steroid
Joint-targeted injection of local anesthetic, steroids, or their combination
Intramuscular injection of local anesthetic with or without steroids
Dorsal root ganglion radiofrequency with or without epidural injection of local anesthetic or local anesthetic plus steroids

These recommendations contradict those of the American Society of Interventional Pain Physicians (ASIPP), a professional organization that represents pain management physicians. The 2021 ASIPP guidelines strongly endorse spinal injections for treating chronic lumbar and cervical pain. In their discussion, the ASIPP authors argue that saline or short-acting local anesthetics, frequently used as controls in steroid injection studies, shouldn't be considered placebos because they have an actual therapeutic effect. They go on to contend that single-arm analysis (i.e., looking at therapies individually without comparing them to a control group) is most telling and should receive the majority of emphasis. Huh?

While it's a little comical and slightly disconcerting that a professional association would make an argument to disregard placebo controls in randomized trials, it's not surprising given that they represent doctors who put their kids through college performing these procedures. It also explains how two professional organizations can come to entirely different conclusions analyzing the same evidence. Like most things in life, all you have to do is follow the money.

NEWS IN BRIEF

New migraine therapies get hypertension and Raynaud's precautions

The FDA recently required that all calcitonin gene-related peptide (CGRP) antagonist therapies, including newer migraine therapies like Aimovig and Nurtec, add precautions about hypertension and Raynaud's phenomenon to their labeling. In postmarketing reports, worsening and new-onset hypertension have been reported in some patients treated with CGRP antagonist therapies. Likewise, new-onset and worsening Raynaud's phenomenon has also been observed. Patients receiving CGRP antagonists should monitor their blood pressure, especially during initiation, and consider discontinuation if significant increases are noted. Caution should be used when prescribing to patients with Raynaud's, and therapy should be discontinued for worsening or new-onset disease.

Saxenda for weight loss in children aged 6 to 12 years

Approximately 21% of children aged 6 to 12 years in the U.S. are obese. Traditional weight-loss therapies, including intensive diet and exercise programs, have shown modest efficacy and limited long-term effects in trials. Saxenda (liraglutide), a once-daily GLP therapy approved for weight loss in adolescents and adults, was recently evaluated in children aged 6 to 12 years with obesity. The SCALE Kids study randomized 82 children (mean age 10) with an average BMI of 31 to Saxenda (target dose of 3 mg) or placebo. After 56 weeks, the primary outcome, percent change in BMI, was -5.8% in the Saxenda group and +1.6% in the placebo group (p<0.001). Percent increase in body weight also favored Saxenda (1.6% vs 10%, p=0.001). Eleven percent of Saxenda-treated patients discontinued therapy because of side effects.

While some providers may cringe at the idea of giving a 6-year-old a daily injection for weight loss, it's important to remember that there is a push in the medical community to recognize obesity as a chronic disease, rather than a lifestyle choice. If this is the case, these types of studies and treatments may become common.

Platelet-rich plasma (PRP) injections do not benefit trochanteric bursitis

Trochanteric bursitis, inflammation of the bursa located between the gluteal tendon and the lateral femur, affects up to 25% of women over the age of 50 and can be difficult to treat. Proponents of platelet-rich plasma (PRP) injections contend that the cytokine-rich solutions stimulate healing and reduce inflammation. To evaluate the effects of PRP injections on trochanteric bursitis, researchers randomized 79 patients with refractory trochanteric bursitis to ultrasound-guided leukocyte-rich PRP injections into the trochanteric bursa and gluteus medius, or placebo. After 12 months, there was no significant difference in a number of pain and function outcomes.

These results are not surprising given the lack of efficacy PRP injections have shown in other placebo-controlled trials. [PMID 34812863, PMID 31748208, PMID 34698782] A previous trochanteric bursitis study comparing steroid injections to physical therapy (PT) found that physical therapy was superior. [PMID 29720374] The PT regimen used in that study is available at the link below. Patients with trochanteric bursitis should skip the injections and focus on strengthening and exercise.

Study evaluates Wegovy for alcohol use disorder

Observational studies suggesting GLP-1 therapies may improve addictive behaviors, including alcoholism, have received significant press. To test these findings, researchers randomized 48 non-treatment-seeking adults with alcohol use disorder to semaglutide (max dose 1 mg weekly) or placebo. At 9 weeks, reductions in voluntary alcohol consumption, as observed in a controlled setting, were greater in the semaglutide group. However, semaglutide did not affect self-reported average drinks per calendar day or number of drinking days.

In this small study, semaglutide reduced the number of drinks consumed in a drinking episode but did not affect the number of drinking days. Study weaknesses include small sample size, missing data from participants who did not participate in the post-treatment session (N=16), and a moderate semaglutide dose. Additionally, outcomes were expressed as regression coefficients, and more intuitive measures (e.g., reduction in number of drinks) were not reported. While this study is encouraging, larger and longer trials are needed to define the role of GLP therapies in alcohol use disorder.

POPULAR PAGES

CHARTS

BASICS

MEDICATIONS

NEW DRUGS

Gepotidacin (Blujepa®) - New antibiotic for UTI
Journavx® (Suzetrigine) - new pain medication with novel mechanism
Vtama® (tapinarof) - topical aryl hydrocarbon receptor (AhR) agonist for psoriasis
Cobenfy® (xanomeline + trospium chloride) - Antipsychotic with novel mechanism
Tryvio® (aprocitentan) - Endothelin receptor antagonist for resistant hypertension
Ebglyss® (Lebrikizumab) - IL-13 inhibitor for atopic dermatitis

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?

Journavx® (suzetrigine), new pain med with a novel mechanism

The FDA recently approved Journavx® (suzetrigine), a novel pain medication with a unique mechanism of action. Suzetrigine is a sodium channel blocker that selectively inhibits NaV1.8 voltage-gated sodium channels, which are expressed in peripheral sensory neurons involved in pain signaling. In a study of 1,118 patients undergoing abdominoplasty, suzetrigine demonstrated similar pain relief to hydrocodone/acetaminophen (5 mg/325 mg every 6 hours) over the first 48 postoperative hours. However, a separate similar study involving 1073 bunionectomy patients found suzetrigine to be superior to placebo but inferior to hydrocodone/APAP.

Suzetrigine's side effect profile is comparable to placebo, and no significant precautions have been identified. The recommended dosage is 100 mg once (on an empty stomach), followed 12 hours later by 50 mg every 12 hours (with or without food). Its use has not been studied beyond 14 days. Suzetrigine is a CYP3A substrate and inducer and should not be administered with strong CYP3A inhibitors. A notable interaction exists with hormonal contraceptives containing progestins other than levonorgestrel and norethindrone. The prescribing information advises that women taking these medications should use additional nonhormonal (e.g., condoms) or alternative contraceptives (e.g., combined oral contraceptives containing levonorgestrel or norethindrone) during treatment and for 28 days after discontinuation.

A novel, non-opioid pain reliever is a significant and much-needed addition. However, like all newly approved drugs, it is expensive and will likely face pushback from insurers. A study comparing it to a high-dose or potent NSAID, such as ketorolac, would be informative.

Zoledronate infusion for fracture prevention in early postmenopausal women

Zoledronate, a bisphosphonate infusion approved to treat osteoporosis, has been shown to prevent fractures in women aged 65 and older with osteopenia (T-score -1 to -2.5). To explore its effects in younger women with bone loss in the osteopenia or less range, researchers randomized 1054 postmenopausal women aged 50 to 60 (average age 56) with a T-score between 0 and -2.5 at the lumbar spine, femoral neck, or total hip (average lumbar spine T-score: -0.43; average total hip T-score: -0.51) to one of three treatments: zoledronate 5 mg at baseline and in 5 years, zoledronate 5 mg at baseline and placebo in 5 years, or placebo at baseline and in 5 years. At 10 years, the primary outcome, morphometric vertebral fracture (fractures identified by their shape on X-ray as opposed to symptoms), occurred in 6.3% (Zoledronate-Zoledronate), 6.6% (Zoledronate-Placebo), and 11.1% (Placebo-Placebo) of patients (p<0.05). Incidences of any fracture were 24.7%, 27.4%., and 35.3%, respectively. (p<0.05). No cases of osteonecrosis of the jaw or atypical femoral fracture, two concerning bisphosphonate side effects, were reported during the trial.

Zoledronate reduced the 10-year fracture risk in postmenopausal women aged 50 to 60 with an average T-score of around -0.46. Two infusions were slightly more effective than one, and both were superior to placebo. A secondary analysis stratifying effect size by baseline bone mineral density (BMD) would have been informative but was not performed. With 45% of women aged 50 to 60 having T-scores less than 0, these results apply to a large population. Current USPSTF guidelines recommend BMD screening in women under 65 at increased risk of osteoporosis, which they loosely define as a 10-year fracture risk of 10% or more.

Providers wanting to incorporate this study into their practice could follow these steps:

Screen postmenopausal women aged 50 to 60 with the FRAX tool
If the 10-year risk of a major osteoporotic fracture is greater than 10%, order a BMD test
If the T-score is 0 to -2.5 at the lumbar spine, femoral neck, or total hip, offer a one-time infusion of zoledronate 5 mg, with an anticipated effect of reducing the absolute risk of any fracture over 10 years by 8%

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.

Recommendations following gastric bypass