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.

• EPIC-CAD - Edoxaban vs Dual Therapy in AF and CAD, NEJM (2924) [PubMed abstract]
• Antiplatelet therapy in CAD

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.

• Finerenone (Kerendia®) review
• Heart failure review

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.

• Ensifentrine (Ohtuvayre®) review
• COPD review

Tirzepatide, the blockbuster GLP/GIP weight-loss drug marketed as Zepbound, was recently compared to placebo in patients with NASH, also known as metabolic dysfunction–associated steatohepatitis or fatty liver disease. The SYNERGY-NASH trial randomized 190 patients with NASH and F2 or F3 fibrosis to three doses of tirzepatide - 5 mg, 10 mg, and 15 mg - or placebo. After 52 weeks, NASH resolution occurred in 44%, 56%, 62%, and 10%, respectively, while a decrease in fibrosis stage of ≥ 1 was seen in 55%, 51%, 51%, and 30% (all tirzepatide-placebo comparisons were significant). Tirzepatide-treated patients lost 11 - 16% of their body weight, depending on the dose. Drug discontinuations due to side effects were rare in all groups (≤4%).

NASH is driven by hepatocellular adiposity, so it is not surprising that tirzepatide-induced weight loss improved liver pathology. In a previous trial, semaglutide was significantly better than placebo for NASH resolution but not fibrosis improvement. [PMID 33185364]

Resmetirom is the only medication currently FDA-approved to treat NASH, and while results from different studies are not comparable linearly, nothing in resmetirom's pivotal trial suggests that it is superior to tirzepatide. Furthermore, it does not cause weight loss, giving it no benefit in other obesity-related conditions.

• Tirzepatide vs Placebo for NASH, NEJM (2024)

In 2011, the Endocrine Society (ES) published vitamin D guidelines that recommended widespread screening and defined normal serum values as > 30 ng/ml. The guidance was harshly criticized for its lack of supporting evidence. Nonetheless, many providers adopted universal screening and recommended supplementation, including large weekly doses, to many patients. Since then, numerous studies have found that vitamin D does not improve outcomes across a broad array of conditions. In response to the new data, the ES recently published updated guidelines, and while they improve on the previous ones, their recommendation for empiric supplementation in certain groups flies in the face of evidence from randomized trials. Significant new recommendations, including links to contradictory evidence, are presented below.

• Screening: Routine vitamin D screening is not recommended in generally healthy adults
• Target levels: There is no clear evidence supporting an optimal vitamin D level
• Supplementation: Empiric supplementation, defined as daily intake of fortified foods and/or supplements containing vitamin D, is recommended in the following groups:
• Ages 1 - 18 years: to prevent nutritional rickets and potentially lower the risk of respiratory tract infections. [Contradictory studies: PMID 32706534, PMID 29813149, PMID 28719693, PMID 22494826]
• Age ≥ 75 years: may lower the risk of mortality [Contradictory study: PMID 35026158]
• Prediabetics: to reduce the risk of progression to diabetes [Contradictory studies: PMID 31173679, PMID 26829443]
• Pregnancy: to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age (SGA) birth, and neonatal mortality [Contradictory studies: PMID 30089075, PMID 26944421]

After years of rampant vitamin D testing and unwarranted treatment, the updated recommendations are welcome. However, the empiric supplementation guidance is not supported by randomized trials and is unlikely to have a meaningful effect.