Primecuts – This Week in the Journals

March 5, 2021

PrimeCuts 8 min read

By Amit Jhaveri, MD

Peer Reviewed

Introduction: With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Primecuts

Glycemic Index, Glycemic Load and Cardiovascular Disease and Mortality  https://www.nejm.org/doi/full/10.1056/NEJMoa2007123?query=featured_cardiology [1] 

Glycemic index represents the rise in blood glucose that may be expected when consuming a fixed amount of a carbohydrate. [2] Glycemic load estimates the actual glycemic response based on the portion of the meal. [3] Current data regarding the association between a diet with low glycemic index and cardiovascular risk are mixed and inconclusive. [4] Further, studies have focused on populations from high-income Western demographics. The authors of this study utilized data from the Prospective Urban Rural Epidemiology study (PURE) to assess glycemic index and load as a risk factor for cardiovascular disease.

This study enrolled 137,851 participants between the ages of 35-71 from 20 countries across 5 continents. Questionnaires were distributed to collect information regarding demography, lifestyle, health history, and medication use. The authors also distributed food-frequency questionnaires to participants. The primary outcome was a composite of major cardiovascular event (cardiovascular death, non-fatal MI, stroke, heart failure), or death from any cause. The median follow up was 9.5 years.

The primary outcome was met in 14,075 participants. A positive association was observed in patients with high glycemic index for those with pre-existing CV disease (HR 1.51 CI 1.25-1.82), those without pre-existing CV disease (HR 1.21 CI 1.11-1.34), and the total population (HR 1.25 CI 1.15-1.37). Glycemic index was also associated with increased risk of death from any cause. These effects were stronger in those with higher BMI (>25) than those < 25 (p=0.01). Exercise status, smoking, or blood-pressure medications or statins played did not demonstrate significant effect on the primary outcome. Glycemic load also portended increased risk of major cardiovascular events and deaths, however only for those with pre-existing cardiovascular disease. This study displayed data to support the notion that diets with high glycemic index are associated with cardiovascular disease. It is unique for its diverse patient inclusion, cultural and economic significance. Limitations to interpretation include its broad population and thus decreased precision in terms of individual foods and across populations.

Avacopan for the Treatment of ANCA-Associated Vasculitis  https://www.nejm.org/doi/full/10.1056/NEJMoa2023386?query=featured_nephrology [5]

ANCA-associated vasculitis is difficult to treat and is associated with complications such as renal dysfunction due to rapidly progressive focal glomerulonephritis. [6] Traditional treatment includes long term use of glucocorticoids which are known to have toxic effects.[7] Pathophysiology of ANCA vasculitis involves the activation of alternative complement pathway and increased C5a production. Thus inhibition of C5a may serve as a potential mechanistic target for treatment of this disease.

Avacopan is a C5a receptor antagonist that blocks neutrophil chemoattraction. This drug has been tested in mice and prevented glomerulonephritis induced by antimyeloperoxidase antibodies.[8] The ADVOCATE trial aims to study the effects of this drug in the treatment of ANCA-associated vasculitis.[9]

This Phase 3 double-blind randomized control trial utilized over 100 international medical centers, allowing recruitment of 331 patients with newly diagnosed or relapsing granulomatosis polyangiitis or microscopic polyangiitis. Patients were randomized to receive 30mg of avacopan twice daily versus prednisone with a tapering regimen. All patients received standard induction therapy with cyclophosphamide and azathioprine, or rituximab. The trials primary endpoints included clinical remission at week 26, and sustained remission at week 26 and 52. Secondary endpoints included glucocorticoid induced toxic effects, relapse, change in baseline eGFR, urinary albumin: creatinine ratio, urinary monocyte chemoattractant protein 1:creatinine ratio, and vasculitis damage index.

Remission at week 26 was seen in 72.3% of patients taking avacopan and 70.1% for those taking prednisone, indicating non-inferiority (Common difference 3.4% CI -6.0 – 12.8 p<0.001). Sustained remission at week 52 was higher for those receiving avacopan (65.7%) versus prednisone (54.9%) (CD 12.5% CI 2.6 – 22.3 p<0.001 NI, p=0.007 superiority). As a secondary outcome, Avacopan also demonstrated benefit to kidney function. In addition, patients in the prednisone group suffered from more deaths (2.4% versus 1.2%), life-threatening or serious adverse events (39% versus 37.3%), and infections (15.2% versus 13.3%), although without statistical significance.

Notably, all patients in this study did receive a brief course of glucocorticoids during the screening or early phase in the trial. However, these data suggest that complement directed therapies may become mainstream for ANCA associated vasculitis, potentially eliminating and avoiding toxic effects of glucocorticoids.

Prognostic Value of Coronary CT Angiography in Patients with Non-ST-Segment-Elevation Acute Coronary Syndromes https://www.jacc.org/doi/10.1016/j.jacc.2020.12.037 [10]

Current guidelines for patients suffering from non-ST elevation acute coronary syndrome (NSTEACS) favor invasive angiography for patients with high risk clinical features and selective invasive strategy for a patient with low risk features. [11] In 2018, the VERDICT trial showed no difference between very early (within 12 hours) and deferred (within 48-72 hours) invasive coronary angiography (ICA) for patients with NSTEACS. [12] This trial included 2,147 patients from 9 hospitals in Copenhagen. Linde et al. subsequently studied a subset of patients from VERDICT and demonstrated that coronary CT angiography (CTA) can be utilized as a tool to rule out obstructive coronary artery disease in NSTEACS. [13]

As further follow up, this study took another subset of 978 patients from VERDICT who underwent both CTA and invasive coronary angiography. The authors tested the hypothesis that CTA is equal to ICA for risk assessment for NSTEACS.

These patients were followed for a mean of 4.2 years. The primary endpoint included all cause death, non-fatal recurrent MI, hospital admission for MI or heart failure. This study found obstructive coronary artery disease in 73.4% of patients with CTA and 66.9% of patients who underwent ICA. High risk lesions, defined as left main stenosis, left anterior descending stenosis, or multi-vessel disease were found in 51% of patients with CTA and 36.8 for those undergoing ICA. Over 4 years 21.3% of patients met the primary endpoint. Both CTA (HR 1.74 CI 1.22-2.49) and ICA (1.54 CI 1.13 – 2.11) predicted the increased risk of meeting the primary endpoint for those with obstructive CAD versus non-obstructive CAD. For those with high risk lesions versus non-high risk, CTA was superior (HR 1.56 CI 1.18-2.07) at predicting increased risk of primary endpoint versus ICA (HR 1.28 CI 0.98-1.69).

This study demonstrates that CTA is equivalent, or perhaps superior to invasive coronary angiography for the identification of coronary artery disease that has prognostic importance. Limitations to the study include the fact that the study only included percent occlusion per vessel and did not include other important information regarding plaque structure that can be derived from CTA. Williams et al. also added a critique of the primary endpoint suggesting that hospitalization for heart failure or recurrent myocardial ischemia may not reflect plaque rupture.[14] Regardless, this study further illuminates the role CTA continues to play for CAD, and now a randomized controlled trial between ICA versus CTA are needed

Minicuts:

Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19 https://www.nejm.org/doi/full/10.1056/NEJMoa2100433?query=featured_home [15]

An important and unanswered question regarding the treatment of COVID-19 involves the role of IL-6 inhibitors. Given the vast inflammatory response seen in this disease process, IL-6 was thought to be attractive target for mediating inflammation. Data thus far has displayed mixed and contradictory results.[16-21] This recent randomized controlled trial, as a part of the REMAP-CAP, studied the use of tocilizumab and sarilumab in critically ill patients. They found that these inhibitors reduced in-hospital mortality (OR 1.64 CI 1.14 – 2.35 for tocilizumab and 2.01 CI 1.18 – 4.71 for sarilumab) and reduced number of time receiving organ support (OR 1.64 CI 1.25 – 2.14 for tocilizumab, 1.76 CI 1.17 – 2.91 for sarilumab). It remains unclear how best to utilize IL-6 inhibition in COVID-19 illness.

Comparative Effectiveness and Harms of Antibiotics for Outpatient Diverticulitis https://www.acpjournals.org/doi/10.7326/M20-6315 [22]

This study compared amoxicillin-clavulanate acid versus metronidazole with fluroquinolone for the treatment of outpatient diverticulitis. They assessed 1-year inpatient admission risk, urgent surgery, Clostridioides difficile infection (CDI) and 3-year risk for elective surgery via retrospective data. 106,361 patients received metronidazole-with-fluroquinolone and 13,160 amoxicillin-clavulanate. No differences in 1-year admission risk (Risk Difference 0.1 CI -0.3-0.6), 1-year urgent surgery (RD 0 CI -0.1-0.1), 3-year elective surgery risk (RD 0.2 CI-0.3-0.7), or 1-year CDI risk (RD 0 CI -0.1 -0.1) were found. For Medicare patients, the 1-year CDI risk was higher for metronidazole with fluroquinolone than for amoxicillin-clavulanate (RD 0.6 CI 0.2-1.0). Thus, amoxicillin-clavulanate acid may be suitable for treatment of diverticulitis in the outpatient setting and may reduce fluroquinolone associated CDI.

Once-Weekly Semaglutide in Adults with Overweight or Obesity https://www.nejm.org/doi/full/10.1056/NEJMoa2032183?utm [23]

This study assessed the role of semaglutide, a GLP-1 agonist, for weight loss in patients with obesity without diabetes mellitus. In this double-blind trial, 1961 adults with BMI greater than 30 were randomized to receive once weekly semaglutide versus placebo for 68 weeks. Those taking semaglutide on average had a mean change in body weight of -14.9% versus -2.4 with placebo with a treatment difference of -12.4 (CI -13.4 to -11.5). In addition, more participants taking semaglutide has larger reductions of 5% or more (86% versus 31.5%), 10% or more (69% versus 12%), and 15% or more (50.5% versus 4.9%). Semaglutide may be a suitable treatment option for patients with obesity even in the absence of diabetes.

Dr. Amit Jhaveri is a 2nd year resident at NYU Langone Health

Peer reviewed by Roisin Finan, MD, section editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

  1. Jenkins DJA, Dehghan M, Mente A, et al. PURE Study Investigators. Glycemic Index, Glycemic Load, and Cardiovascular Disease and Mortality. N Engl J Med. 2021 Feb 24. doi: 10.1056/NEJMoa2007123. Epub ahead of print. PMID: 33626252.
  2. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL, Goff DV. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981 Mar;34(3):362-6. doi: 10.1093/ajcn/34.3.362. PMID: 6259925.
  3. Salmerón J., Manson J.E., Stampfer M.J., Colditz G.A., Wing A.L., Willett W.C. Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women. 1997;227:472–477. doi: 10.1001/jama.1997.03540300040031
  4. Vega-López S, Venn BJ, Slavin JL. Relevance of the Glycemic Index and Glycemic Load for Body Weight, Diabetes, and Cardiovascular Disease. Nutrients. 2018;10(10):1361. Published 2018 Sep 22. doi:10.3390/nu10101361
  5. Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609. doi: 10.1056/NEJMoa2023386. PMID: 33596356.
  6. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med1988;318:1651-1657.
  7. Jayne D. Evidence-based treatment of systemic vasculitis. Rheumatology (Oxford) 2000;39:585-595.
  8. Xiao H, Dairaghi DJ, Powers JP, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol2014;25:225-231.
  9. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol2017;28:2756-2767.
  10. Kofoed KF, Engstrøm T, Sigvardsen PE, et al. Prognostic Value of Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol. 2021 Mar 2;77(8):1044-1052. doi: 10.1016/j.jacc.2020.12.037. PMID: 33632478.
  11. Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2020 Aug 29 [E-pub ahead of print].
  12. Kofoed KF, Kelbæk H, Hansen PR, et al. Early versus standard care invasive examination and treatment of patients with non-ST-segment elevation acute coronary syndrome: the VERDICT (Very Early vs Deferred Invasive Evaluation Using Computerized Tomography) randomized controlled trial. 2018;Epub ahead of print.
  13. Linde JJ, Kelbæk H, Hansen TF, et al. Coronary CT angiography in patients with non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2020;Epub ahead of print
  14. Williams MC, Dweck MR, Newby DE. Coronary computed tomography angiography to triage patients with non–ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2021;77:1053-1056.
  15. REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Feb 25. doi: 10.1056/NEJMoa2100433. Epub ahead of print. PMID: 33631065.
  16. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med2020;383:2333-2344
  17. Hermine O, Mariette X, Tharaux P-L, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med2021;181:32-40.
  18. Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med2021;181:24-31.
  19. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021;384:20-30.
  20. Rosas IO, Bräu N, Waters M, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med. DOI: 10.1056/NEJMoa2028700.
  21. Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomized controlled trial. BMJ2021;372:n84-n84.
  22. Gaber CE, Kinlaw AC, Edwards JK, et al. Comparative Effectiveness and Harms of Antibiotics for Outpatient Diverticulitis : Two Nationwide Cohort Studies. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315. Epub ahead of print. PMID: 33617725.
  23. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Feb 10. doi: 10.1056/NEJMoa2032183. Epub ahead of print. PMID: 33567185.