Background. To characterize the association of antiretroviral drug combinations on risk of cardiovascular events. Methods. Certain antiretroviral medications for human immunodeficiency virus (HIV) have been implicated in increasing risk of cardiovascular disease. However, antiretroviral drugs are typically prescribed in combination. We characterized the association of current exposure to antiretroviral drug combinations on risk of cardiovascular events including myocardial infarction, stroke, percutaneous coronary intervention, and coronary artery bypass surgery. We used the Veterans Health Administration Clinical Case Registry to analyze data from 24 510 patients infected with HIV from January 1996 through December 2009. We assessed the association of current exposure to 15 antiretroviral drugs and 23 prespecified combinations of agents on the risk of cardiovascular event by using marginal structural models and Cox models extended to accommodate time-dependent variables. Results. Over 164 059 person-years of follow-up, 934 patients had a cardiovascular event. Current exposure to abacavir, efavirenz, lamivudine, and zidovudine was significantly associated with increased risk of cardiovascular event, with odds ratios ranging from 1.40 to 1.53. Five combinations were significantly associated with increased risk of cardiovascular event, all of which involved lamivudine. One of these—efavirenz, lamivudine, and zidovudine—was the second most commonly used combination and was associated with a risk of cardiovascular event that is 1.60 times that of patients not currently exposed to the combination (odds ratio = 1.60, 95% confidence interval, 1.25–2.04). Conclusions. In the VA cohort, exposure to both individual drugs and drug combinations was associated with modestly increased risk of a cardiovascular event.

BACKGROUND: Previous studies comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary disease not involving the left main have shown significantly lower rates of death, myocardial infarction (MI), or stroke after CABG. These studies did not routinely use current-generation drug-eluting stents or fractional flow reserve (FFR) to guide PCI. METHODS: FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) is an investigator-initiated, multicenter, international, randomized trial involving patients with 3-vessel coronary artery disease (not involving the left main coronary artery) in 48 centers worldwide. Patients were randomly assigned to receive FFR-guided PCI using zotarolimus drug-eluting stents or CABG. The prespecified key secondary end point of the trial reported here is the 3-year incidence of the composite of death, MI, or stroke. RESULTS: A total of 1500 patients were randomized to FFR-guided PCI or CABG. Follow-up was achieved in >96% of patients in both groups. There was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% versus 9.2%; hazard ratio [HR], 1.3 [95% CI, 0.98–1.83]; P =0.07). The rates of death (4.1% versus 3.9%; HR, 1.0 [95% CI, 0.6–1.7]; P =0.88) and stroke (1.6% versus 2.0%; HR, 0.8 [95% CI, 0.4–1.7]; P =0.56) were not different. MI occurred more frequently after PCI (7.0% versus 4.2%; HR, 1.7 [95% CI, 1.1–2.7]; P =0.02). CONCLUSIONS: At 3-year follow-up, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI with current-generation drug-eluting stents compared with CABG. There was a higher incidence of MI after PCI compared with CABG, with no difference in death or stroke. These results provide contemporary data to allow improved shared decision-making between physicians and patients with 3-vessel coronary artery disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02100722.

BACKGROUND: Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive. METHODS: Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit. RESULTS: Our cohort ( n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution. CONCLUSION: We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04373148. FUNDING: NIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

It has been well established that randomized clinical trials have poor external validity, resulting in findings that may not apply to relevant—or target—populations. When the trial is sampled from the target population, generalizability methods have been proposed to address the applicability of trial findings to target populations. When the trial sample and target populations are distinct, transportability methods may be applied for this purpose. However, generalizability and transportability studies present challenges, particularly around the strength of their conclusions. We review and summarize state-of-the-art methods for translating trial findings to target populations. We additionally provide a novel step-by-step guide to address these challenges, illustrating principles through a published case study. When conducted with rigor, generalizability and transportability studies can play an integral role in regulatory decisions by providing key real-world evidence.

Background: The Apple watch irregular pulse detection algorithm was found to have a positive predictive value of 0.84 for identification of atrial fibrillation (AF). We sought to describe the prevalence of arrhythmias other than AF in those with an irregular pulse detected on a smartwatch. Methods: The Apple Heart Study investigated a smartwatch-based irregular pulse notification algorithm to identify AF. For this secondary analysis, we analyzed participants who received an ambulatory ECG patch after index irregular pulse notification. We excluded participants with AF identified on ECG patch and described the prevalence of other arrhythmias on the remaining participant ECG patches. We also reported the proportion of participants self-reporting subsequent AF diagnosis. Results: Among 419 297 participants enrolled in the Apple Heart Study, 450 participant ECG patches were analyzed, with no AF on 297 ECG patches (66%). Non-AF arrhythmias (excluding supraventricular tachycardias <30 beats and pauses <3 seconds) were detected in 119 participants (40.1%) with ECG patches without AF. The most common arrhythmias were frequent PACs (burden ≥1% to <5%, 15.8%; ≥5% to <15%, 8.8%), atrial tachycardia (≥30 beats, 5.4%), frequent PVCs (burden ≥1% to <5%, 6.1%; ≥5% to <15%, 2.7%), and nonsustained ventricular tachycardia (4–7 beats, 6.4%; ≥8 beats, 3.7%). Of 249 participants with no AF detected on ECG patch and patient-reported data available, 76 participants (30.5%) reported subsequent AF diagnosis. Conclusions: In participants with an irregular pulse notification on the Apple Watch and no AF observed on ECG patch, atrial and ventricular arrhythmias, mostly PACs and PVCs, were detected in 40% of participants. Defining optimal care for patients with detection of incidental arrhythmias other than AF is important as AF detection is further investigated, implemented, and refined.