Notably, the 2018 guideline identified fewer younger adults eligible for statin therapy at the time of their MI than the 2013 guideline (46.4% vs. 56.7%; p<0.01). Younger patients were found to less frequently meet very high-risk criteria for intensive secondary prevention lipid-lowering therapy (28.3% vs. 40.0% for middle-aged vs. 81.4% for older patients; p<0.01).

Furthermore, the authors found that over a median eight years of follow-up, younger individuals with very high-risk criteria were associated with increased risk of major adverse cardiovascular events in individuals younger than 55 years (hazard ratio, 2.09; 95% confidence interval 1.82-2.41; p<0.001), as was the case in older age groups (p for interaction = 0.54).

"To our knowledge, this is among the first studies to evaluate statin guideline eligibility comprehensively with a focus on premature heart disease since the release of the most recent cholesterol guideline and implementation of risk enhancers," the authors write. "Previous studies demonstrated that older cholesterol guidelines frequently failed to assign primary prevention statins to young individuals at risk of acute MI… our results demonstrate that the situation has not improved under the 2018 guideline."

In a related editorial comment, Ron Blankstein, MD, FACC, and Avinainder Singh, MD, MMSC, note that "it is apparent that there are many more opportunities to reduce the risk of MI beyond just cholesterol-lowering agents." They add, "Ultimately, greater primordial and primary prevention efforts are needed. If our goal is to achieve the greatest possible reduction in cardiovascular events, we should not miss any opportunities to improve prevention."

Zeitouni M, Nanna MG, Sun J-L, et al. J Am Coll Cardiol 2020;76:653-64.

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Of the 12,042 patients eligible for matching, 11,834 patients were matched with 47,336 individuals from the background population (median age, 42.6 years, 54.3% men). The median follow-up was 8.2 years. Results showed absolute 10-year risk of outcomes were:

• HF: 3.18% in sarcoidosis and 1.72% in controls.
• Composite of ICD implantation, ventricular arrhythmias, cardiac arrest: 0.96% in sarcoidosis and 0.45% in controls.
• Composite of pacemaker implantation, atrioventricular block, sinoatrial dysfunction: 0.94% in sarcoidosis and 0.51% in controls.
• Atrial fibrillation or flutter: 3.44% in sarcoidosis and 2.66% in controls.
• All-cause mortality: 10.88% in sarcoidosis and 7.43% in controls.

"[Patients] with sarcoidosis developing HF had a higher associated mortality than patients with HF without a history of sarcoidosis," write the authors. "These findings warrant further large-scale studies on the risk and prognosis associated with adverse cardiac outcomes in patients with sarcoidosis, including patients with confirmed cardiac sarcoidosis."

"These findings support the need for monitoring for cardiac manifestations in patients with systemic sarcoidosis," write Melissa A. Lyle, MD, FACC, and Leslie T. Cooper Jr., MD, FACC, in an accompanying editorial comment. "Future management guidelines for cardiac sarcoidosis should include these data for developing recommendations regarding the role of advanced imaging modalities and biopsy for diagnosis, prognosis, and treatment."

Yafasova A, Fosbol EL, Schou M, et al. J Am Coll Cardiol 2020;76:767-77.

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Compared with trials in higher-risk groups, the sample sizes in the low-risk populations were smaller and the number of primary endpoint events was lower (193 in low-risk vs. 615 in high-risk trials).

According to Kaul, this suggests an "insufficient quantum of evidence" to recommend TAVR in low-risk patients. Kaul also writes the trial design for the low-risk cohorts was "less robust." He notes that PARTNER 2, which tested TAVR in an intermediate-risk group, had a primary endpoint of death or disabling stroke vs. a primary endpoint of death, any stroke or rehospitalization for PARTNER 3.

In addition, PARTNER 3 had a shorter follow-up and wider noninferiority margin. The low-risk trials had different key outcomes despite similar baseline cardiovascular risk, which could "challenge generalizability," Kaul writes.

According to Kaul, the "totality of evidence does not support endorsing TAVR as the preferred therapy" for low-risk patients." The "quantum of evidence" needed to extend TAVR guideline recommendations to these patients should "be based on stringent trial design utilizing unbiased primary endpoints and longer follow-up without modeling outcomes via imputation," he concludes.

"A balance needs to be struck between generating the most robust evidence possible in a reasonable time frame and with realistic funding, all while generating meaningful findings that are likely to impact clinical practice," Michael J. Mack, MD, MACC, and David H. Adams, MD, FACC, write in a Counterpoint.

Controversy regarding the outcomes of comparative trials often concern the trial's design, which is often not widely known before a trial begins. It is thus, "imperative that all stakeholders scrutinize the various aspects of trial design and endpoints" early enough to allow investigators an opportunity to reconsider the design, and potentially make changes that would strengthen the study," they conclude.

Kaul S. J Am Coll Cardiol 2020;76:985-91. Mack MJ, Adams DH. J Am Coll Cardiol 2020;76:992-5.

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Compared with patients with ≤Mild TR, among those with ≥Moderate TR, NYHA class III/IV HF and a Society of Thoracic Surgeons score ≥8 were more common, along with anemia, chronic kidney disease and a higher NT-proBNP. Patients with ≥Moderate TR had more severe MR and higher right ventricular systolic pressure.

Among patients treated with GDMT alone, the composite rate of death or HF hospitalization (HFH) at two years was higher for those with ≥Moderate TR vs. ≤Mild TR (83.0% vs. 64.3%; hazard ratio [HR, 1.74; 95% confidence interval [CI], 1.24-2.45; p=0.001). For patients treated with MitraClip, rates of the composite outcome were 48.2% vs. 44.0%, respectively (HR, 1.14; 95% CI, 0.71-0.84; p=0.59). Rates of death or HFH, as well as death and HFH alone, were reduced by MitraClip compared with GDMT, regardless of baseline TR grade.

The authors write, "In the COAPT trial of patients with [HF] and severe secondary MR who remained symptomatic despite maximally tolerated GDMT, the concomitant presence of moderate or severe TR at baseline was associated with more severe MR, higher pulmonary pressures, and worse [HF] signs and symptoms." They note that although the MitraClip seems to mitigate adverse outcomes associated with baseline TR, "further research is needed to determine whether concomitant or sequential treatment of TR can improve outcomes further."

In an accompanying editorial comment, Yee-Ping Sun, MD, FACC, writes, "Once considered the 'forgotten valve,' it is now clear that tricuspid regurgitation has important prognostic significance, with significant impact on clinical management." Sun also notes, "The experienced multidisciplinary heart team is now more important than ever as we strive to achieve the results seen in COAPT."

Hahn RT, Asch F, Weissman NJ, et al. J Am Coll Cardiol 2020;76:1305-14.

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Over a median follow-up of 2.6 years, there were 93 deaths with an estimated five-year survival of 79%. Both TRF and TRVol were associated with mortality after adjustment of clinical and imaging variables, including RV function.

"A TRVol of ≥45 ml or TRF of ≥50% had the greatest risk for excess mortality under medical management, with an [adjusted hazard ratio] of 2.3 and 2.6 compared with a TRVol of <30 ml of TRF of <30%, respectively," write the authors. "Future randomized controlled trials using these thresholds will determine if tricuspid valve intervention may benefit this high-risk group."

"This study provides the best evidence to date that severe TR has an independent effect on outcome and highlights the advantages of the accurate assessment of both the TR and RV function," writes Saul G. Myerson, MB CHB, MD, in an accompanying editorial comment. "This may facilitate better identification of patients most likely to benefit from percutaneous tricuspid valve intervention.

However, the benefit of treatment with percutaneous devices will need confirmation in randomized clinical trials – even the best statistical techniques cannot completely remove the confounding effects of RV dilation and dysfunction."

Zhan Y, Debs D, Khan MA, et al. J Am Coll Cardiol 2020;76:1291-1301.

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After adjustment, the authors found that progressively higher levels of LDL-C were associated with a higher incidence of late cardiovascular events. Compared with LDL-C <70 mg/dL, the hazard ratios for cardiovascular events were 1.17 (95% CI, 1.09-1.26) for LDL-C of 70 to >100 mg/dL, and 1.78 (95% CI, 1.64-1.94) for LDL-C ≥100 mg/dL.

"Our findings suggest that improved cholesterol management after PCI, which could include routine check of LDL-C levels and increased use of statin therapy, may lead to improved patient outcomes," the authors conclude.

In a related editorial comment, Robert S. Rosenson, MD, FACC, et al., writes, "There is an urgent need for implementing strategies that mandate systems approaches to more frequent monitoring of LDL-C, and a patient-physician/health care provider dialog that fosters health through lifestyle modifications, adherence to high-intensity statins and other class I preventive therapies, and use of non-statin medications to lower LDL-C in patients with suboptimal LDL-C lowering on maximum tolerated statins."

Sud M, Han L, Koh M, et al. J Am Coll Cardiol 2020;76:1440-50.

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Of the 4,041 patients in the COMPLETE trial, QCA was performed in 3,851 patients with 5,355 nonculprit lesions. Of these, 2,627 had one nonculprit lesion and 1,224 had two or more nonculprit lesions. QCA stenosis was severe in 2,479 patients and moderate in 1,372 patients. Those with severe QCA stenosis were less likely to smoke but more likely to have hypertension, dyslipidemia or elevated body mass index.

Among the 2,479 patients with severe stenosis, incidence of cardiovascular death or MI was 2.5% per year in those with complete revascularization vs. 4.2% per year in those with culprit-lesion-only PCI (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.47-0.79). In the 1,372 patients with moderate stenosis, cardiovascular death or MI was 3% per year among those with complete revascularization and 2.9% per year in those with culprit-lesion-only PCI (HR, 1.04; 95% CI, 0.72-1.50).

Regarding the second coprimary outcome of cardiovascular death, MI or IDR, in patients with severe stenosis, incidence was 2.9% per year for those receiving complete revascularization vs. 6.9% per year in those receiving culprit-lesion-only PCI (HR, 0.43; 95% CI, 0.34-0.54). In patients with moderate stenosis, the second coprimary outcome occurred at a rate of 3.3% per year for those with complete revascularization and 5.3% per year for those with culprit-lesion-only PCI (HR, 0.65; 95% CI, 0.47-0.89). For propensity matching, 1,225 patients with moderate stenosis were matched to 2,137 patients with severe stenosis. There were similar results in the matched population.

The findings "provide insight" into how nonculprit-lesion stenosis severity may affect PCI in patients with STEMI and multivessel coronary artery disease," write the authors. Additional research is needed to evaluate other methods of identifying nonculprit lesions for treatment, they note. In an accompanying editorial comment Sanjay Kaul, MD, writes the results "highlight some of the major caveats that challenge interpretation of subgroup analyses" and should be used "for informing future research" rather than "to guide clinical practice."

Sheth T, Pinilla-Echeverri N, Moreno R, et al. J Am Coll Cardiol 2020;76:1277-86.

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Of the 34,926 patients enrolled in GARFIELD-AF, 10,426 received a DOAC. Of these, 72.9% received recommended dosing, 23.2% were underdosed and 3.8% were overdosed. Nonrecommended dosing was associated with a higher risk of all-cause mortality. The risk of stroke/systemic embolism and major bleeding was not significantly different based on the level of dosing.

"Treatment above the recommended doses was relatively rare compared with non-recommended dosing," write the authors of the study. "Of those who were treated over the recommended doses, 67.5% had moderate to severe [chronic kidney disease], as opposed to 8.6% of patients with recommended dosing and 7.1% of patients with underdosing. The highest risk patients were more prone to receive nonrecommended doses of DOACs."

"Treating patients is an art and clinicians may rarely need to individualize a treatment for a given patient," writes Gerald V. Naccarelli, MD, FACC, in an accompanying editorial comment. "However, the clinician should be careful with the art of practice. Ignoring the truth of the well-studied and [recommended] doses of DOACs can lead to dangerous consequences. The truth is that these doses have not been well-studied and exposes patients to thromboembolic events leading to a stroke. Primum non-nocere (first do no harm) is part of the original Hippocratic oath. Under-dosing of a DOAC may break this tenet."

Camm AJ, Cools F, Virdone S, et al. J Am Coll Cardiol 2020;76:1425-36.

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