Much like the successful splashdown of Artemis II, The Rounds Report returns to your inbox.

And it's a good one.

Forty years of reflexive post-MI beta-blockers. Challenged. A pulmonary embolism trial that finally moves the needle beyond anticoagulation alone. The first oral GLP-1 to beat semaglutide head-to-head. And — at long last — a treatment that actually works for long COVID fatigue.

This quarter's evidence is consequential and broad, cutting across the subspecialties you manage every day. From the CCU to the general medicine ward to the outpatient clinic, these five studies will change how you talk to patients, round with trainees, and reach for the prescription pad.

Here's what you need to know.

1. HI-PEITHO: Catheter-Directed Thrombolysis Redefines Intermediate-Risk PE Management

For years, intermediate-risk PE has lived in an uncomfortable gray zone — too sick for heparin alone, too stable for systemic lysis. HI-PEITHO just gave us a third option.

544 patients with intermediate-high-risk PE were randomized at 59 centers to ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, or anticoagulation alone. The primary composite of PE-related death, cardiopulmonary decompensation or collapse, or symptomatic PE recurrence at 7 days: 4.0% versus 10.3% — a 61% relative risk reduction (P=0.005; NNT 16). No intracranial hemorrhages in either arm. Alteplase doses were modest: 8.85 mg unilateral, 16.92 mg bilateral.

Practice implication: Intermediate-risk PE represents 25–30% of every PE you admit. Expect rapid PERT protocol expansion and guideline updates in the coming months. Note: the trial was industry-sponsored by Boston Scientific, which manufactures the EKOS device used in the intervention arm.

HI-PEITHO Trial - NEJM

2. SMART-DECISION: Time to Reconsider Long-Term Beta-Blockers After MI

SMART-DECISION randomized 2,540 stable post-MI patients with LVEF ≥40%, no heart failure, and no atrial fibrillation (on beta-blockers ≥1 year; median 4.7 years post-MI) to discontinuation versus continuation. At median 3.1 years, the primary composite of death, recurrent MI, or HF hospitalization: 7.2% versus 9.0% (HR 0.80; 95% CI 0.57–1.13; P=0.001 for noninferiority).

Practice implication: Beta-blockers remain indicated for reduced EF, heart failure, and arrhythmias. For the stable, preserved-EF post-MI majority — the bulk of patients you discharge — the evidence for indefinite continuation has evaporated.

SMART-DECISION Trial - NEJM

3. ACHIEVE-3: The Oral GLP-1 That Doesn't Require Fasting Just Beat Semaglutide

Orforglipron — a small-molecule oral GLP-1 with no fasting requirement — outperformed oral semaglutide head-to-head in 1,698 adults with type 2 diabetes on metformin (mean HbA1c 8.3%). At 52 weeks, orforglipron 36 mg achieved HbA1c reduction of 1.91% versus 1.47% with semaglutide 14 mg (difference −0.44%; P<0.0001), and weight loss of 9.2% versus 5.3%. HbA1c ≤6.5% achieved in 68% versus 48%. The tradeoff: GI adverse events and treatment discontinuation were modestly higher with orforglipron (9–10% vs 4–5%).

Practice implication: No cardiovascular outcomes data yet. But as a small molecule — not a peptide — orforglipron could eventually reach patients currently priced out of GLP-1 therapy entirely. Worth watching the real-world tolerability data as it matures.

ACHIEVE-3 Trial - The Lancet

4. REVIVE-TOGETHER: Fluvoxamine Is the First Proven Treatment for Long COVID Fatigue

399 adults with post-COVID fatigue (FSS ≥4, persisting 90 days to 1 year) were randomized to fluvoxamine 100 mg twice daily, metformin, or placebo for 60 days. Fluvoxamine achieved a mean FSS difference of −0.43 (95% CrI −0.80 to −0.07; 99% posterior probability of benefit), deepening to −0.58 at day 90. Participants were ~50% more likely to achieve fatigue recovery (FSS <3). The metformin arm was stopped for futility. Adverse events were lower with fluvoxamine (20.0%) than placebo (29.7%).

Practice implication: For internists fielding long COVID questions daily, this is the first pharmacotherapy backed by Level 1 evidence. The mechanism is likely sigma-1 receptor–mediated anti-inflammatory activity rather than antidepressant effect — patients with major depressive disorder were excluded from the trial.

REVIVE-TOGETHER Trial - Annals of Internal Medicine

5. CORALreef AddOn: An Oral PCSK9 Inhibitor That Matches Injectable Efficacy

Enlicitide, a once-daily oral PCSK9 inhibitor, was compared against bempedoic acid, ezetimibe, and their combination in 301 statin-treated high-risk adults. At 56 days, enlicitide reduced LDL-C by 64.6% (95% CI −68.3 to −60.9) versus −6.3%, −27.8%, and −36.5% for comparators (all P<0.001). 81.2% of enlicitide patients achieved LDL <70 mg/dL with ≥50% reduction, versus 2–22% in comparator arms.

Practice implication: With the 2026 ACC/AHA guidelines now targeting LDL <55 mg/dL for very-high-risk patients, an oral pill approaching injectable efficacy is a meaningful access shift for the millions blocked by cost, injection hesitancy, or prior authorization fatigue. Cardiovascular outcomes data are pending through 2029.

CORALreef AddOn - JACC

Pulmonary/Critical Care

Cardiology

Endocrinology

Infectious Disease / Long COVID

Neurology

Rheumatology

Oncology/Screening

Geriatrics/General IM

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