Can my patient with renal insufficiency safely undergo gadolinium-based contrast MRI?

It may be possible for patients with renal insufficiency, including those with end-stage kidney disease (ESKD), to undergo MRI using potentially safer preparations of gadolinium-based contrast agents (GBCAs) with “very low, if any” risk of the feared nephrogenic systemic sclerosis (NSF). 1

In contrast to the so called “linear” chelates of gadolinium (eg, gadodiamide, gadopentetate), “cyclic” GBCA’s (eg, gadoteridol) have not been clearly associated with NSF. 2 A Veterans Administration study involving gadoteridol identified no cases of NSF among the 141 patients on hemodialysis following 198 exposures. 2 In fact, the 2017 American College of Radiology (ACR) Manual on Contrast Media reports the risk of NSF with cyclic chelates as “very low, if any”. 1 Even when a cyclic GBCA is used in patients with ESKD, however, hemodialysis is recommended as soon as possible after MRI. 3

GBCAs are chelates with 2 major components: gadolinium and either a linear or cyclic ligand. Cyclic ligands bind to gadolinium more avidly, resulting in lower probability of circulating renally-cleared free gadolinium which when deposited in tissue is thought to potentially trigger NSF.2

Although NSF is characterized by progressive fibrosis of skin and soft tissue, it may involve multiple organs with an estimated 30% mortality rate. 4

 Bonus Pearl: Did you know NSF is really a new disease, with no evidence of its existence before 1997?

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References

  1. “Nephrogenic Systemic Fibrosis”. In ACR Manual on Contrast Media; Version 10.3; May 31, 2017. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf
  2. Reilly RF. Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol 2008;3:747-51. https://www.ncbi.nlm.nih.gov/pubmed/18287249
  3. Wang Y, Alkasab TK, Nari O, et al. Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines. Radiology 2011;260:105-111.  https://www.ncbi.nlm.nih.gov/pubmed/21586680
  4. Schlaudecker JD, Bernheisel CR. Gadolinium-associated nephrogenic systemic fibrosis. Am Fam Physician 2009;80:711-14. https://www.aafp.org/afp/2009/1001/p711.pdf

 

Contributed by Richard Newcomb, MD, Mass General Hospital, Boston, MA.

Can my patient with renal insufficiency safely undergo gadolinium-based contrast MRI?

Why isn’t my patient with congestive heart failure or end-stage liver disease losing weight despite being on diuretic therapy? Is the diuretic dose too low, or is the salt intake too high?

When a patient with congestive heart failure (CHF) or end-stage liver disease (ESLD) doesn’t respond as expected to diuretic therapy, measurement of urinary sodium (Na) can be helpful.

In low effective arterial blood volume states (eg, CHF and ESLD) aldosterone secretion is high, resulting in high urine potassium (K) and low urine Na concentrations. However, in the presence of diuretics, urinary Na excretion should rise.

Patients undergoing active diuresis are often restricted to a 2 g (88 mEq) Na intake/day, with ~10 mEq excreted via non-urinary sources (primarily stool), and ~ 78 mEq excreted in the urine to “break even” — that is, to maintain the same weight.

Although historically measured 1, a 24-hour urine Na and K collection is tedious, making spot urine Na/K ratio more attractive as a potential proxy.  Approximately 90% of patients who achieve a urinary Na/K ratio ≥1 will have a urinary Na excretion ≥78 mEq/day — that is to say, they are sensitive to the diuretic and will have a stable or decreasing weight at the current dose. 2,3

Urine Na/K may be interpreted as follows:

  • ≥1 and losing weight suggests effective diuretic dose, adherent to low Na diet
  • ≥1 and rising weight suggests effective diuretic dose, non-adherent to low Na diet
  • <1 and rising weight suggests ineffective diuretic dose

The “ideal” Na/K ratio as relates to responsiveness to diuretics has ranged from 1.0 to 2.5.4 In acutely decompensated heart failure patients on spironolactone, a K-sparing diuretic, Na/K ratio >2 at day 3 of hospitalization may be associated with improved outcome at 180 days. 5

Remember also that if the patient’s clinical syndrome is not correlating well with the ratio, it’s always a good idea to proceed to a 24-hour urine collection.

 

References

  1. Runyon B. Refractory Ascites. Semin Liver Dis. Semin Liver Dis. 1993 Nov;13(4):343-51. https://www.ncbi.nlm.nih.gov/pubmed/8303315
  2. Stiehm AJ, Mendler MH, Runyon BA. Detection of diuretic-resistance or diuretic-sensitivity by spot urine Na/K ratios in 729 specimens from cirrhotics with ascites: approximately 90 percent accuracy as compared to 24-hr urine Na excretion (abstract). Hepatology 2002; 36: 222A.
  3. da Silva OM, Thiele GB, Fayad L. et al. Comparative study of spot urine Na/K ratio and 24-hour urine sodium in natriuresis evaluation of cirrhotic patients with ascites. GE J Port Gastroenterol 2014;21:15-20 https://pdfs.semanticscholar.org/4dc3/4d18d202c6fa2b30a1f6563baab80d877921.pdf
  4. El-Bokl M, Senousy, B, El-Karmouty K, Mohammed I, Mohammed S, Shabana S, Shelby H. Spot urinary sodium for assessing dietary sodium restriction in cirrhotic ascites. World J Gastroenterol 2009; 15:3631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721236/
  5. Ferreira JP, Girerd N, Medeiros PB, et al. Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect. Clin Res Cardiol 2016;105:489-507. https://www.ncbi.nlm.nih.gov/pubmed/26615605

 

Contributed by Alyssa Castillo, MD, with valuable input from Sawalla Guseh, MD, both from Mass General Hospital, Boston, MA.

Why isn’t my patient with congestive heart failure or end-stage liver disease losing weight despite being on diuretic therapy? Is the diuretic dose too low, or is the salt intake too high?

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

Although its mechanism is not full elucidated, fixed drug eruption (FDE) is thought to result from the drug-induced cytotoxic activation of CD8+ memory T cells.1 ,2

In this context, the culprit medication behaves as a hapten that adheres to basal keratinocytes which in turn results in the recruitment of T cells and inflammation.  However, as the inflammation resolves, CD8+  effector-memory T cells remain in the area in question,  setting the stage for more rapid immunologic reaction when the drug is reintroduced.

Why a systemic drug triggers a reaction only at specific sites in the body is a fascinating question. Prior herpes simplex virus (HSV) infection (eg, on the lips or genitalia) may explain some cases.1 Interestingly, despite the absence of prior herpetic lesions, most patients with FDE are seropositive for HSV. Previously traumatized body sites (e.g. from burns or insect bites) may also create an immune microenvironment conducive to FDE.

The classic presentation of FDE is reappearance of a rash in the genitals, perianal areas, hands, and feet within 30 min to 8 hours of taking the culprit medication.3 Look specifically for NSAIDs, tetracyclines, sulfonamides, and aspirin on the patient’s drug list. 4

References

  1. Shiohara, T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009; 9:316-21. https://www.ncbi.nlm.nih.gov/pubmed/19474709
  2. Butler, DF. Fixed Drug Eruptions. Medscape. http://emedicine.medscape.com/article/1336702-overview#a4. Accessed March 26, 2018.
  3. Korkij W, Soltani K. Fixed drug eruptions: A brief review. Arch Dermatol 1984;120:520. https://www.ncbi.nlm.nih.gov/pubmed/6231004
  4. Oakley, A. Fixed Drug Eruption. https://www.dermnetnz.org/topics/fixed-drug-eruption Accessed March 26, 2018.

 

Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

What is the connection between methemoglobinemia and hemolytic anemia?

Methemoglobinemia coupled with hemolytic anemia (HA) has been reported under different clinical scenarios and may have therapeutic implications for treatment of methemoglobinemia in the setting of G6PD deficiency.

Increased methemoglobin levels have been observed during the hemolytic crisis of patients with favism due to G6PD deficiency. This finding has been attributed to excessive oxidative stress generated by divicine, an oxidizing constituent of fava beans, and the inability to reduce its stress because of an insufficient G6PD-dependent hexose monophosphate shunt. 1Hemolytic anemia may also follow drug-induced methemoglobinemia, especially with exposure to dapsone, sulfasalazine, or phenacetin, and may be a feature of hemoglobin MSaskatoon and MHyde Park , abnormal hemoglobin variants associated with genetic methemoglobinemia. 2The concurrence of hemolysis due to G6PD deficiency and methemoglobinemia is not just an academic curiosity and may in fact pose a therapeutic quandary. This is because methylene blue, the treatment of choice for methemoglobinemia, is also an oxidant and works only after it is reduced to leukomethylene blue by (you guessed it!) nicotinamide adenine nucleotide phosphate (NADPH), a G6PD-dependent process. 2,3 With plenty of methylene blue on hand and little leukomethylene around in G6PD-deficiency, treatment may be ineffective or even cause worsening of methemoglobinemia. It’s never simple!

Final fun fact: Did you know that methylene blue is the first synthetic drug (>100 years ago) and has been used in the prevention of UTIs in the elderly, and treatment of pediatric malaria and Alzheimer’s disease? 4References

  1. Schuurman M, van Waardenburg D, Da Costa J, et al. Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphate dehydrogenase: Case report and literature review. Eur J Ped 2009;168:779-782. https://link.springer.com/article/10.1007/s00431-009-0952-x
  2. Rehman HU. Methemoglobinemia. West J Med 2001;175:193-96. https://www.researchgate.net/publication/11817876_Methemoglobinemia
  3. Hassan KS, Al-Riyami AZ, Al-Huneini M, et al. Methemoglobinemia in an elderly patient with glucose-6-phosphate dehydrogenase deficiency: A case report. Oman Med J 2014;29:135-37. https://squ.pure.elsevier.com/en/publications/methemoglobinemia-in-an-elderly-patient-with-glucose-6-phosphate-
  4. Schirmer RH, Adler H, Pickhardt M, et al. “Lest we forget you—Methylene blue…” Neurobiology of Aging 2011; 32:2325. https://www.ncbi.nlm.nih.gov/pubmed/21316815
What is the connection between methemoglobinemia and hemolytic anemia?

Should prothrombin complex concentrates be used to reverse anticoagulation from direct factor Xa inhibitors?

Due to insufficient and occasionally conflicting evidence, the use of prothrombin complex concentrates (PCCs) for reversal of direct factor Xa inhibitors (eg, rivaroxaban, apixaban, and edoxaban) is NOT recommended.1 This is because PCCs have no effect on the anti-Xa assay, the most accurate measure of anticoagulation for direct factor Xa inhibitors.

Although several in vitro and in vivo studies initially suggested that PCCs may be effective for this purpose, anti-Xa activity has not been measured in these studies2-4; PT and aPTT are not reflective of the anticoagulation activity of direct factor Xa inhibitors.

In fact, a 2014 study found no difference in the anti-Xa activity between 11 patients on rivaroxaban who were given a 4-factor PCC (Beriplex®, the European brand name for Kcentra®) and 12 patients on rivaroxaban receiving saline.5 Though small, this is the best published in vivo data to date examining the effect of 4-factor PCC on the anti-Xa levels of patients on direct factor Xa inhibitors.

A theoretical concern with the use of PCCs is increased risk of thrombosis when the therapeutic effect of these direct oral anticoagulant (DOACs) is gone (half-life ~12 h) while the thrombogenic effects of PCCs persist (eg, in critically ill, postoperative, or sedentary patients).

The good news is that more specific reversal agents are in the pipeline. 1 Stay tuned! 

 

References:

  1. Dzik WH. “Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal.” J Thromb Haemost 2015;13 (Suppl 1):S187-94. https://www.ncbi.nlm.nih.gov/pubmed/26149022
  2. Perzborn E, Heutmeier S, Laux V, et al. “Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro.” Thromb Res 2014 Apr;133:671-81. https://www.ncbi.nlm.nih.gov/pubmed/24529498
  3. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. “Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.” Circulation 2011 Oct 4;124:1573-9. https://www.ncbi.nlm.nih.gov/pubmed/21900088
  4. Zahir H, Brown KS, Vandell AG, et al. “Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate.” Circulation 2015 Jan 6;131:82-90. https://www.ncbi.nlm.nih.gov/pubmed/25403645
  5. Levi M, Moore KT, Castillejos CF, et al. “Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers.” J Thromb Haemost 2014;12:1428-36. https://www.ncbi.nlm.nih.gov/pubmed/24811969

Contributed by Hanny Al-Samkari MD, Mass General Hospital, Boston, MA.

 

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Should prothrombin complex concentrates be used to reverse anticoagulation from direct factor Xa inhibitors?

Is iron therapy contraindicated in my patient with active infection?

In the absence of randomized-controlled trials of iron therapy in patients with active infection, the harmful effects of iron therapy (IT) in this setting remains more theoretical than proven. 1,2

Although many pathogens (eg, E. coli, Klebsiella, Salmonella, Yersinia, and Staphylococcus species) depend on iron for their growth2,3, and iron overload states (eg, hemochromatosis) predispose to a variety of infections, studies evaluating the risk of infection with iron therapy have reported conflicting results.1-4 A 2015 systematic review and meta-analysis of 103 trials comparing IV iron therapy  with several other approaches, including oral iron therapy or placebo, found no increased risk of infections with IV iron.5 In contrast, an earlier systematic review and meta-analysis involving fewer number of trials found an increased risk of infections with IV iron. 6

These varied results are perhaps not surprising since the effects of iron therapy on the risk of infection is likely to be context-specific, depending on the patient’s preexisting iron status, exposure to potential infections and co-infection and genetic background. 4 Of interest, mice with sepsis have worse outcomes when treated with IV iron.7

Perhaps the most prudent approach is to hold off on iron therapy until the active infection is controlled, unless the benefits of urgent iron therapy is thought to outweigh its theoretical harmful effects.

 

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References

  1. Daoud E, Nakhla E, Sharma R. Is iron therapy for anemia harmful in the setting of infection? Clev Clin J Med 2011;78:168-70. http://www.mdedge.com/ccjm/article/95480/hematology/iron-therapy-anemia-harmful-setting-infection
  2. Hain D, Braun M. IV iron: to give or to hold in the presence of infection in adults undergoing hemodialysis. Nephrology Nursing Journal 2015;42:279-83. https://www.ncbi.nlm.nih.gov/pubmed/26207288
  3. Jonker FAM, van Hensbroek MB. Anaemia, iron deficiency and susceptibility of infections. J Infect 204;69:523-27. https://www.ncbi.nlm.nih.gov/pubmed/28397964
  4. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012;338:768-72. https://www.ncbi.nlm.nih.gov/pubmed/23139325  
  5. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc 2015;90:12-23. http://www.mayoclinicproceedings.org/article/S0025-6196(14)00883-0/pdf
  6. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomized clinical trials. BMJ 2013;347:f4822. https://www.ncbi.nlm.nih.gov/pubmed/23950195
  7. Javadi P, Buchman TG, Stromberg PE, et al. High dose exogenous iron following cecal ligation and puncture increases mortality rate in mice and is associated with an increase in gut epithelial and splenic apoptosis. Crit Care Med 2004;32:1178-1185. https://www.ncbi.nlm.nih.gov/pubmed/15190970
Is iron therapy contraindicated in my patient with active infection?

My hospitalized patient has developed acute nausea, vomiting, and diarrhea. Is there an association between proton pump inhibitors and acute gastroenteritis?

 

Proton pump inhibitors (PPIs) have been associated with increased risk of Clostridium difficile infection, as well as acute gastroenteritis (AG) caused by Salmonella, Campylobacter, and most recently, norovirus. 1,2

A recent prospective study1 of over 38,000 patients (mean age ~ 70 y) found a significant association between PPI use and AG leading to hospitalization with a dose-response relationship.  PPI use increased the risk of Salmonella, Campylobacter, and C. difficile infections.  Of note, H2 receptor antagonists were not associated with AG-related hospitalization in this study.

A 2017 retrospective case-control study also showed an association between PPI use and norovirus infection in hospitalized patients (mean age ~80 y in both groups). Most cases occurred during epidemic years with a median hospital stay of 5 days before onset of symptoms. Given the usually short incubation period of norovirus AG (typically 12-48 h), many of these cases likely acquired the infection during their hospital stay.

Besides reducing the acidity of gastric juice, PPIs may increase the risk of AG by causing an overgrowth of bacteria in the GI tract, reduce its motility and adversely affect the immune response, including neutrophil chemotaxis. 3

Does your patient really need a PPI?

 

References

  1. Chen Y, Liu B, Glass K, et al. Use of proton pump inhibitor and the risk of hospitalization for infectious gastroenteritis. PLoS One 2016;11:e0168618. Doi:10.1371/journal.pone. 0168618.   http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168618    
  2. Prag C, Prag M, Fredlund H. Proton pump inhibitors as a risk factor for norovirus infection. Epidemiol Infect 2017;145:1617-23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426289/pdf/S0950268817000528a.pdf
  3. Wandall JH. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. Gut 1992;33:617-21. https://www.ncbi.nlm.nih.gov/pubmed/1319381
My hospitalized patient has developed acute nausea, vomiting, and diarrhea. Is there an association between proton pump inhibitors and acute gastroenteritis?

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

 

Patients with atrial fibrillation (AF) who need percutaneous coronary intervention (PCI) after acute coronary syndrome or for stable angina pose a treatment challenge as oral anticoagulants (OACs) and dual antiplatelet therapy (DAPT) are often used concurrently to decrease the risk of systemic thromboembolism and stent thrombosis. However, “triple therapy”, including aspirin, a P2Y12 inhibitor, and an OAC (eg, warfarin or a direct oral anticoagulant-DOAC), also increases the risk of bleeding, necessitating several recent landmark trials to better address the subject.

Two modest-sized RCTs (WOEST and ISAR-TRIPLE) reported that when compared to triple therapy (DAPT plus warfarin), double therapy (single antiplatelet agent plus INR-targeted warfarin) is associated with reduced risk of bleeding complications without an increased risk of thrombotic events. 1,2

Two larger RCTs, PIONEER AF-PCI and RE-DUAL PCI, studied rivaroxaban and dabigatran, respectively, in patients with non-valvular AF undergoing PCI and found a reduction in bleeding events in patients receiving double therapy (single antiplatelet agent plus DOAC) compared to triple therapy (DAPT plus warfarin), without an increased risk of thrombotic complications. 3,4

Collectively, these studies suggest that it may be safe to treat patients with increased risk of bleeding with double therapy (even immediately following PCI) without an increase in thrombotic events. If triple therapy is elected, duration should be minimized, clopidogrel should be preferred over more potent P2Y12 inhibitors, and a PPI should be considered.

 

References:

  1. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381:1107-15. https://www.ncbi.nlm.nih.gov/pubmed/23415013
  2. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65:1619-29. https://www.ncbi.nlm.nih.gov/pubmed/25908066
  3. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1611594
  4. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. Published online, Aug, 27, 2017. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708454

 

Contributed by Amulya Nagarur, MD, Mass General Hospital, Boston, MA

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

Evidence supporting the efficacy of direct oral anticoagulants (DOACs) in obesity is limited. A major concern is the possibility of subtherapeutic anticoagulation in obese patients when standard doses of DOACs are used.

The International Society on Thrombosis and Haemostasis recommends1:

  • Standard fixed dosing of DOACs for patients with BMI ≤ 40 kg/m2 or weight ≤ 120 kg.
  • Avoiding DOACs in patients with BMI > 40 kg/m2 or weight > 120 kg. However, if a DOAC is needed, laboratory confirmation of therapeutic drug concentrations (eg, by checking anti-factor Xa depending on the agent) should be performed, and if subtherapeutic, a vitamin K antagonist (eg, warfarin) is recommended instead.

Based on the individual comparison of DOACs with warfarin in patients with “high” body weight (cut-off of 90 kg or 100 kg, depending on the study) and limited data, apixaban may be more effective in preventing recurrent venous thromboembolism or its related deaths. However, other DOACs, such as rivaroxaban, dabigatran, and edoxaban have also been used in patients with high body weight2.  

To add to the controversy, the efficacy of fixed dose dabigatran in obese patients has been questioned3 and some have recommended avoiding DOACs altogether in patients with BMI ≥ 35 kg/m2 or weight > 120 kg, until more data become available4.

As in many situations in medicine, a case-by-case decision based on clinical judgment and patient preferences may be the best way to go!

References

  1. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 1308–13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936273
  2. Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med 2015; 47: 61-8. https://www.ncbi.nlm.nih.gov/pubmed/25665582
  3. Breuer L, Ringwald J, Schwab S, et al. Ischemic Stroke in an Obese Patient Receiving Dabigatran. N Engl J Med 2013; 368: 2440–2. http://www.nejm.org/doi/pdf/10.1056/NEJMc1215900
  4. Burnett AE, Mahan CE, Vasquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE Treatment. J Thromb Thrombolysis 2016; 41: 206-32. https://www.ncbi.nlm.nih.gov/pubmed/26780747

 

Contributed by Mahesh Vidula, MD, Mass General Hospital, Boston, MA.

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

The weight of the evidence suggests that methotrexate reduces the overall risk of cardiovascular events (CVEs)—including myocardial infarction, congestive heart failure, stroke, and or major adverse cardiac events—in RA patients (RR 0.72, 95% CI 0.57-0.91)1.

Aside from its effect on controlling systemic inflammation, methotrexate has also been shown to increase HDL and reduce total cholesterol/HDL ratio in patients with RA compared with treated non-RA controls2. In vitro, methotrexate appears to activate mechanisms involved in reverse transport of cholesterol out of the cell to the circulation for eventual excretion3. Not surprisingly then, methotrexate has also been reported to decrease atherosclerotic plaque burden measured by carotid artery intima-media thickness2.

We tend to think of RA as a disease that primarily causes arthritis but its effects may extend far beyond the joints. Patients with RA have an increased risk of cardiovascular deaths compared to the general population4, likely due to a variety of factors, including accelerated atherosclerosis secondary to chronic inflammation. At baseline, RA patients also have an unfavorable lipid profile with decreased HDL and higher total cholesterol/HDL ratio.

Fun Final Fact: Did you know that methotrexate is on the WHO Model List of Essential Medicines (April 2015) not only as a cancer drug but for treatment of RA as well5?

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References:

  1. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, Gulliver W, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480-9. https://www.ncbi.nlm.nih.gov/pubmed/25561362
  2. Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 2008;38:13-9. https://www.ncbi.nlm.nih.gov/pubmed/18191989
  3. Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H, Fernandez P, Cronstein BN, Chan ES. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 2008;58:3675-83. https://www.ncbi.nlm.nih.gov/pubmed/19035488
  4. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7. https://www.ncbi.nlm.nih.gov/pubmed/19035419
  5. WHO Model List of Essential Medicines (April 2015). http://www.who.int/medicines/publications/essentialmedicines/en/

 

Contributed by Brian Li, Medical Student, Harvard Medical School

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?