Doxycycline is an old tetracycline-like antibiotic with a comparatively good side-effect profile, but it doesn’t get much love in the guidelines for community-acquired pneumonia as the evidence level was deemed to be low. A recent issue of Clinical Infectious Diseases contained a systematic review with a meta-analysis.

Dr. Brad Spellberg is the chief medical office at the Los Angeles County-University of Southern California Medical Center. Dr. Spellberg is also a professor of clinical medicine and the associate dean for clinical affairs at the USC’s Keck School of Medicine.

I talk with him about why doxy might be a good CAP drug (and when it is not a good choice), guidelines and the process of creating guidelines, and resistance patterns, MICs, and clinical significance.

References:

-Shorter Is Better: https://www.bradspellberg.com/shorter-is-better

-Oral Is the New IV: https://www.bradspellberg.com/oral-antibiotics

-WikiGuidelines: https://www.wikiguidelines.com/

-SH Choi et al.: Clin Infect Dis. 2022 Jul 29;ciac615. https://pubmed.ncbi.nlm.nih.gov/35903011/

-NICE: Pneumonia (community-acquired): antimicrobial prescribing. Published: 16 September 2019. https://www.nice.org.uk/guidance/ng138

-JP Metlay et al. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67. doi: 10.1164/rccm.201908-1581ST. https://pubmed.ncbi.nlm.nih.gov/31573350/

YouTube channel: https://www.youtube.com/@IMJournalClub

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The NordICC Study is the first randomized controlled trial to test colonoscopy as a screening modality for colorectal cancer. The effect of colonoscopy was lower than previously thought.

We talk with the P.I., Dr. Michael Bretthauer, what to make of the study and whether (and in which areas) we should remain doubtful. Dr. Bretthauer is a professor of medicine at the University of Oslo.

References:

• M Bretthauer et al. N Engl J Med. 2022 Oct 27;387(17):1547-1556. https://pubmed.ncbi.nlm.nih.gov/36214590/
• RL Siegel et al. CA Cancer J Clin. 2022;72:7-33. https://pubmed.ncbi.nlm.nih.gov/35020204/
• Ø Holme et al. Ann Intern Med. 2018;168:775-82. https://pubmed.ncbi.nlm.nih.gov/29710125/
• Global Cancer Observatory, https://gco.iarc.fr/
• M Bretthauer et al. Ann Int Med. 2017;166:139-40. https://pubmed.ncbi.nlm.nih.gov/27820949/
• USPSTF: JAMA. 2021;325(19):1965-77 https://jamanetwork.com/journals/jama/fullarticle/2779985
• E Quintero et al. N Engl J Med. 2012;366:697-706 https://pubmed.ncbi.nlm.nih.gov/22356323/
• AB Knudsen et al. JAMA. 2021;325(19):1998-2011 https://pubmed.ncbi.nlm.nih.gov/34003219/
• Ex. calculator: https://ccrisktool.cancer.gov/calculator.html
• LM Helsingen et al. BMJ. 2019367:l5515. https://pubmed.ncbi.nlm.nih.gov/31578196/

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So, this trial might appear a bit boring and maybe not so relevant – but maybe only at first. What might add to the difficulty reading or interpreting it is the non-inferiority design – and we might to a methods primer on that in the future. However, this trial may be the answer for a very important question: what do we do with patients who are intolerant to higher doses of statins – can a statin-sparing regimen be the answer?

This was a randomized controlled trial of a high-intensity statin, rosuvastatin 20mg daily vs a moderate-intensity statin – 10mg of rosuvastatin daily – plus 10mg of ezetimibe or Zetia. The trial recruited 3,780 patients with atherosclerotic cardiovascular disease and followed them for three years. The primary endpoint was the composite of cardiovascular death, major adverse cardiovascular events, or non-fatal stroke, and was reached in 9.9% in the high-intensity statin group vs 9.1% in the combination group.

Our guest is Christopher P. Cannon, M.D. He is a cardiologist at Brigham and Women’s Hospital in Boston and a professor at Harvard Medical School. He has run major trials of statins and other interventions to prevent major adverse cardiovascular (and cerebrovascular) events, including the IMPROVE-IT study.

References:

• RACING Study: BK Kim et al.: Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial. Lancet. 2022 Jul 30;400(10349):380-90. https://pubmed.ncbi.nlm.nih.gov/35863366/
• IMPROVE-IT: CP Canon et al.: Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med . 2015 Jun 18;372(25):2387-97. https://pubmed.ncbi.nlm.nih.gov/26039521/
• DI Swerdlow et al.: HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015; 385: 351-61. https://pubmed.ncbi.nlm.nih.gov/25262344/
• SU Khan et al.: Association of Lowering Low-Density Lipoprotein Cholesterol With Contemporary Lipid-Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2019;8:e011581. https://pubmed.ncbi.nlm.nih.gov/30898075/
• MG Silverman et al.: Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions. A Systematic Review and Meta-analysis. JAMA. 2016;316(12):1289-97. https://pubmed.ncbi.nlm.nih.gov/27673306/
• PM Ridker et al.: Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. https://pubmed.ncbi.nlm.nih.gov/28845751/
• Y Ouchi et al.: Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial. Circulation. 2019.140(12):992-1003. https://pubmed.ncbi.nlm.nih.gov/31434507/

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Today we are back with another bonus episode: To speak with Simon Sinek, we want to start with the WHY.

Why should we do journal clubs?

Why might be interesting, maybe even necessary?

Why could it even be fun?

Some of this episode - the parts about Newton, Imatinib, "medical reversal", the exponential growth of the medical literature, and how many original articles are publishes each month in just four general medicine journals - is based on a talk that was given by Ben at Mass General Hospital, Boston MA on March 6, 2019 (HMU Pulse Foundational series).

Here are the slides: https://www.slideshare.net/bengggggg/interpreting-the-medical-literature

Check our the end of the pod for our vacancy notice: we're looking for HELP

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Is Vitamin D supplementation useless to prevent fractures in the general population?

While there is currently insufficient evidence to prove that Vitamin D supplementation might prevent cancer or cardiovascular events, several meta-analyses have shown a benefit of Vitamin D plus calcium to prevent hip fractures. This was also seen in a per-protocol analysis of a Women’s Health Initiative study.

The Vitamin D and Ometa-3 Trial or VITAL was a randomized placebo-controlled trial of cholecalciferol (that’s Vitamin D3) and omega-3 fatty acids. Since they tested two interventions, this was studied in two-by-two factorial design. Vitamin D was given as 2000 units daily and the daily omega-3 pills contained 1g of fatty acids. This was an ancillary study of a trial that is hypothesized to test whether these interventions, alone or together, can prevent cancer and cardiovascular disease. The study population is men over 50 and women over 55. There were no other in- or exclusion criteria except that patients could not already have cancer or cardiovascular disease, and also they couldn’t have hypercalcemia.

The study population had a mean age of 67, 51% were female. They recruited entirely in the U.S. and they had 71% Caucasians and 20% African Americans. Notably, it was allowed that patients were already taking Vitamin D supplements, and 43% already did so. 5% were taking osteoporosis medications and 10% had a previous frigitilty fracture. The baseline mean vitamin D level was over 30 ng/ml.

Over the course of the median 5.3 years of follow-up, Vitamin D did not prevent fractures in the total fracture group. The same was true for non-vertebral and hip fractures subgroups.

Our guest, WuQiang Fan, M.D., Ph.D., is an endocrinologist and hospitalist at Mass General Hospital and an Instructior in Medicine at Harvard Medical School. He often functions in the role of the Fracture Liaison Services, seeing patients with a new fracture in consultation, where he might be asked to assess what preventative therapies patients might quality for.

References:

-MS LeBoff et al.. N Engl J Med . 2022 Jul 28;387(4):299-309. https://pubmed.ncbi.nlm.nih.gov/35939577/

-USPSTF: Final Recommendation Statement. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/vitamin-d-calcium-or-combined-supplementation-for-the-primary-prevention-of-fractures-in-adults-preventive-medication

-USPSTF: Final Recommendation Statement. Vitamin D Deficiency in Adults: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/vitamin-d-deficiency-screening (retrieved Nov 11, 2022)

-MF Holick, […], Endocrine Society. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. https://pubmed.ncbi.nlm.nih.gov/21646368/

-NEJM Journal Watch Clincal Conversations. Podcast 297, July 29, 2022. https://pca.st/fhr0cdyo

-Three previous meta-analyses in osteoporotic women that included Vitamin D and calcium:

1) MJ Bolland et al.: Calcium intake and risk of fracture: systematic review . BMJ . 2015 Sep 29;351:h4580. https://pubmed.ncbi.nlm.nih.gov/26420387/

2) DIPART Group. BMJ. 2010;340:b5463. https://pubmed.ncbi.nlm.nih.gov/20068257/

3) A Avenell, JC Mak, and D O'Connell. Cochrane Database Syst Rev. 2014. https://pubmed.ncbi.nlm.nih.gov/24729336/

RD Jackson et al. N Engl J Med. 2006 Feb 16;354(7):669-83. https://pubmed.ncbi.nlm.nih.gov/16481635/

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We are proud to bring you our first methods primer!

We will consider methods primers whenever we cover a study with a more an usual or slightly more complicated methods.

Last week's network-meta-analysis on DVT prophylaxis with Dr. Tony Breu should certainly qualify!

Meta-analysis (both the classical one and the network type) can provide a quantitative synthesis of controlled studies (e.g., randomized controlled trials).

NETWORK meta-analysis can help with two additional things:

1. Through indirect treatment comparison (or a combination of indirect and direct comparison) it can increase your statistical power and
2. It can also help with comparisons that would otherwise not be possible.

Our methods consultant for this first primer on more an usual or slightly more complicated methods is Professor Dr. Ulrich Mansmann, the chair of the Institute for Epidemiology, Biometry, and Medical Information Processing of LMU Munich (Germany).

After covering some basics, we later dive a bit deeper into network meta-analysis.

References:

• T Bartmus, U Mansmann: A Systematic Review and Network Meta-Analysis Assessing the Effectiveness and Tolerability of Gliptins and Sulfonylureas as Monotherapy in Patients with Type 2 Diabetes Mellitus If Metformin is not Considered Appropriate. Value Health. 2014 Nov;17(7):A333. https://pubmed.ncbi.nlm.nih.gov/27200582/
• RJ Eck, T Elling, AJ Sutton et al. Anticoagulants for thrombosis prophylaxis in acutely ill patients admitted to hospital: systematic review and network meta-analysis. BMJ 2022;378:e070022 https://www.bmj.com/content/378/bmj-2022-070022
• F Song et al.: Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ . 2003 Mar 1;326(7387):472. doi: 10.1136/bmj.326.7387.472. https://pubmed.ncbi.nlm.nih.gov/12609941/
• L Mbuagbaw et al.: Approaches to interpreting and choosing the best treatments in network meta-analyses. Syst Rev . 2017 Apr 12;6(1):79. doi: 10.1186/s13643-017-0473-z. https://pubmed.ncbi.nlm.nih.gov/28403893/

YouTube video: https://youtu.be/e_1mvGL8oDk

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After a hiatus over the summer, IM Journal Club is back! Today’s topic might be both very familiar but also somewhat mysterious to all who treat patients in hospitals: deep vein thrombosis (DVT) prophylaxis with subcutaneous injections (daily or more frequent shots). A new network meta-analysis with one slightly different endpoint was published a few months ago in the BMJ – will it end up changing everything?

Our guest speaker couldn’t be more qualified to talk about the new DVT study. Dr. Anthony C. Breu is a Hospitalist at the VA in Boston and an Assistant Professor at Harvard Medical School. He became well known in the med ed community for his tutorials on Twitter ("tweetorials") and for co-editing the Journal for Hospital Medicine’s Things We Do For No Reason series. Together with Drs. Hannah Abrams and Avraham Cooper, he hosts the Curious Clinicians Podcast where he asks "why" a lot.

0:00 Intro

0:34 Plugs

1:10 Why Should Clinicians be Curious?

2:31 Today's Study

22:30 Ben's Take-aways and Outro

References:

-Dr. Breu’s Twitter: https://twitter.com/tony_breu

-Tweetorial on κ/λ ratio in end-stage renal disease: https://twitter.com/tony_breu/status/1572231208599277568

-The Curious Clinicians. A Medical Podcast that asks “Why”? https://curiousclinicians.com/

-RJ Eck, T Elling, AJ Sutton et al. Anticoagulants for thrombosis prophylaxis in acutely ill patients admitted to hospital: systematic review and network meta-analysis. BMJ 2022;378:e070022 https://www.bmj.com/content/378/bmj-2022-070022

-Things We Do For No Reason series: https://twitter.com/twdfnr

Risk stratification tools:

- Check your electronic health record (EHR) system and consider using the built-in system (if there is one)

- S Barbar et al: A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost . 2010 Nov;8(11):2450-7 https://pubmed.ncbi.nlm.nih.gov/20738765/

-M Vardi et al: Venous thromboembolism and the utility of the Padua Prediction Score in patients with sepsis admitted to internal medicine departments. J Thromb Haemost. 2013 Mar;11(3):467-73. https://pubmed.ncbi.nlm.nih.gov/23279085/

-Calculator for the Padua Prediction Score for Risk of VTE: https://www.mdcalc.com/calc/2023/padua-prediction-score-risk-vte

- P Chopard, D Spirk, H Bounameaux: Identifying acutely ill medical patients requiring thromboprophylaxis. J Thromb Haemost. 2006 Apr;4(4):915-6. https://pubmed.ncbi.nlm.nih.gov/16634771/

-M Nendaz et al.: Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE). Thromb Haemost. 2014 Mar 3;111(3):531-8. https://pubmed.ncbi.nlm.nih.gov/24226257/

-Calculator for the Geneva Risk Score for Venous Thromboembolism (VTE) Prophylaxis: https://mdcalc.com/calc/10073/geneva-risk-score-venous-thromboembolism-vte-prophylaxis

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