M-O-U-S-E? No.


The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will inhibit growth of a certain microbe.  In the United States, the Clinical and Laboratory Standards Institute (CLSI) provides standardization of MIC determinations and publish guidelines regularly (the European organization is EUCAST).  Each antimicrobial listed in a culture report will be assigned one of three breakpoints determined by CLSI: “susceptible,” “intermediate,” or “resistant.” 

Many factors, including laboratory and clinical information, determine the interpretation of reported MIC breakpoints.  The term “breakpoint” can be thought of three different, yet interrelated, ways. A microbiologic breakpoint is determined by a multitude of in vitro tests evaluating the physical interaction of the drug with the microbe.  A clinical breakpoint factors in whether there is a good chance of infection resolution, mainly based off of clinical studies.  Similar to a clinical breakpoint, pharmacokinetic/pharmcodynamic breakpoints factor for such things as location of infection and ability to obtain proper drug levels in that area of the body.

Let us use the drug daptomycin for a VRE pneumonia as an example.  The drug may have excellent bacteriocidal activity against the specific cultured organism in vitro, but when factoring in clinical and PK/PD data, we know lung surfactant inactivates daptomycin.  We would not be able to successfully treat the infection with this antimicrobial agent.  The MIC report might state “susceptible” in vitro, but clinically it may as well be regarded as resistant. 

Sooo…can’t I just pick the drug with the lowest number next to it that says “susceptible?”

Apples and oranges, my friend.  It is not useful to compare the MIC concentration value of one drug to another.  The MIC expressed in “mg/L” is unique to each drug based off of PK/PD data done with fancy modeling and simulations.  The determination of what concentrations to use when setting up dilutions to test MICs incorporate things like protein binding, tissue distribution, and even the type of bug that was cultured.  Let’s look at an example:

Source: Urine

E. coli >100,000/mL

Status: Final



>/= 16






</= 0.5



</= 2



</= 32



</= 8



Just strictly looking at numbers, it appears ciprofloxacin would be better than the rest since its MIC is </= 0.5 mg/L.  Nitrofurantoin, even though the report says susceptible, has a larger MIC concentration of </= 32 mg/L.  Both would eradicate this microbe with similar efficacy.  Cefazolin has a value of 4 mg/L.  Notice that it does not have the “</=” designation.  This means the MIC for cefazolin is right at the breakpoint of susceptible and intermediate – an MIC of 8 mg/L may read as intermediate.  The number would still be less than 32 such as for nitrofurantoin but would possibly have less chance of clearing the infection.  Also note that resistance is reported for an MIC of 16 for ampicillin.  Even though it is less than 32, the likelihood of ampicillin clearing the infection would be low.

The key to correctly interpreting this data is to also incorporate antimicrobial stewardship.  If this is an otherwise healthy young female with an uncomplicated cystitis, nitrofurantoin should be the drug of choice.  Although other antibiotics are listed as “susceptible,” it’s like using a shotgun when a Nerf gun would do the job.  Nitrofurantoin is only used for this indication and should be considered first.  Ciprofloxacin would cure the infection and isn’t wrong to use in this situation, but we should preserve our use of it for silly things like anthrax and pseudomonas.


Bottom Line:

  • Interpreting culture results appropriately requires an appreciation for the microbe species and location of infection
  • Comparing MIC concentrations between different drugs is like comparing apples and oranges
  • Utilizing an antibiotic with the “</=” designation may be your best bet
  • Exercise antimicrobial stewardship and choose the lowest-spectrum antimicrobial that will get the job done
  • Consult your friendly pharmacist for assistance


Bugs 'n' Drugs: Vancomycin Dosing


"Hey, Daddy-O.  Are you hip to that newfangled antibiotic, vancomycin?  That stuff is Fat City for beta-lactamase-producing bacteria," said every 1950s physician everywhere.

Ah, a simpler time.  One could just give a patient 1 gram every 12 hours and they'd be riding on easy street.  Today we have some scary bugs and not enough antibiotics to cover them.  To further complicate things, we are struggling with the phenomenon of the vancomycin MIC creep - it means our vancomycin susceptibilities are worsening.  The worst thing our 1950s counterparts had to worry about was not letting "Rock 'n' Roll" poison America's youth.  It's too late for that, but it's not too late to optimize our vanco dosing strategies to help decrease resistance!  Hooray!

Vancomycin is a weird drug.  The pharmacokinetics and dynamics are a bit more complex than other medications.  For instance, it is neither fully a time-dependent antibiotic (beta-lactams), nor a fully concentration-dependent antibiotic (aminoglycosides).  Many different kinetic models have been proposed, but the general consensus is that it involves the ratio of the area under the drug concentration-versus-time curve and the MIC.  We call it the AUC/MIC ratio.

This simply means the trough level we obtain is a marker for an appropriate AUC/MIC ratio.  We know that we need to target a trough of 10 mg/L for a bug with an MIC <1.  The trough required for an MIC = 1 is around 15 mg/L.  As the MIC approaches 2 or more, we can no longer use vanco as a treatment option.  We are seeing MICs of 1 and 1.5 far more than we previously have.  Two ways of combating the vancomycin MIC creep is to do the standard antimicrobial stewardship (no more vanco x1 dose and d/c on oral antibiotics), and appropriately dose the drug.  

Due to the complex kinetics involved, there are a multitude of dosing strategies.  Each institution may do things differently based on practicality and accuracy of the pharmacy kinetic team.  However, each strategy is based off of two things: body weight and renal function.

Standard Method:

  • Most common dosing technique
  • Load 20-25 mg/kg (max. 2000 mg)
  • 15 mg/kg at various intervals (every 8, 12, 24, etc. hours) based on renal function

Our pharmacy uses the Rodvold Method with a couple twists.  This is based of off years of kinetic data and how our pharmacy team has done in regards to obtaining a target trough.  I won't bore you with the details, but just know we rarely do a loading dose and rarely dose at 8-hour intervals.

I'll cut to the chase.  1,000 mg of vanco is not a one-size fits all dose.  We have to be sure we are setting up these patients for success during their hospital course.  Here is my recommendation for when your friendly ER pharmacists are not around: 

  • To the right of the vanco order in our system, click on the grey box with the ellipsis in it.  Select "Vanco Rx to Dose."  The RN will then call down to the main pharmacy where our team will conjure up a dose using our vanco voodoo.
  • Dose it yourself. It's super fun! I recommend a 15-20 mg/kg one-time dose using actual body weight, rounded to the nearest 250mg.  We will take care of the dosing interval when it gets continued in-house.  

Bottom line:

  • Vanco dosing is patient-specific
  • 15-20 mg/kg one-time dose with a max of 2 grams, or
  • Utilize "pharmacy to dose" function
  • Under-dosing vanco will increase the time required to get to a therapeutic trough
  • One gram q12h for everyone is not recommended






No More Nitro

The truth is sometimes I enjoy a good medication shortage.  It forces us to come off of autopilot and think through the goals of therapy and how we can achieve them now that a commonly-used medication is unavailable.  Think about how much fun you all had using ketamine when we had a benzo shortage!  Shortages force us to get comfortable with unfamiliar medications, and look at you all now!  I’d be surprised to hear that one of you hasn’t used ketamine in some fashion.  Groovy stuff!

Shortages also create the opportunity to revisit the evidence behind certain therapies in order to reserve the medication for the most appropriate patients.  Who knows, you might uncover something that changes your practice.  Let’s take a look at what some smart people have to say about IV nitroglycerin use in acute decompensated heart failure:

Heart Failure Society of America 2010 Guidelines

Intravenous vasodilators (nitroprusside, nitroglycerin, or nesiritide) may be considered in patients with ADHF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies.  

Nitroprusside (Strength of Evidence = B)  

Nitroglycerin, Nesiritide (Strength of Evidence = C) 

Intravenous vasodilators (nitroglycerin or nitroprusside) and diuretics are recommended for rapid symptom relief in patients with acute pulmonary edema or severe hypertension. (Strength of Evidence = C)    

European Heart Failure 2012 Guidelines

An i.v. infusion of a nitrate should be considered in patients with pulmonary congestion/edema and a systolic blood pressure >110 mmHg, who do not have severe mitral or aortic stenosis, to reduce pulmonary capillary wedge pressure and systemic vascular resistance. Nitrates may also relieve dyspnea and congestion (Class IIb, Level of Evidence B).   

ACCF/AHA Heart Failure 2013 Guidelines

Intravenous nitroglycerin, nitroprusside, or nesiritide may be considered an adjuvant to diuretic therapy for stable patients with HF (Class IIb, Level of Evidence A).    

I’m seeing a lot of nesiritide and nitroprusside talk along with this nitroglycerin (and shocked to see an A rating on evidence from ACCF/AHA).  When we look at the references cited for grouping nitroglycerin in with the other two medications, we find that there is VERY sparse data for nitro.  It’s all nesiritide and nitroprusside data. For nitro, there’s one nonrandomized, open-label, feasibility study of high-dose bolus nitro in 29 patients, and a 1998 Israeli study of 104 patients that is riddled with protocol violations.  There is one other trial comparing nesitiride vs. nitro called the VMAC study.  Spoiler alert: nesiritide outcompeted nitroglycerin.

If you are scared of the potential adverse events of nesiritide (elevated serum creatinine, questionable trend towards mortality in a meta analysis) or nitroprusside (thiocyanate toxicity…SUPER rare), know that nitroglycerin has potential harm as well.  In fact, in that VMAC study, more patients in the nitro group experienced adverse effects than with nesiritide.  Also, 7-day and 6-month mortalities were similar in the nitro and nesiritide group for VMAC.  Thirty-day readmission was similar with both as well.

Nitro tolerance and resistance are also big problems not seen with the other two.  Initially a benefit may be seen but over the course of hours, there may be no further improvement with subsequent increases in dose.

Additionally, keep in mind that many of these studies occurred before BiPAP became more popular for managing heart failure patients (we thought it led to a higher mortality, then it seemed to reduce mortality, now it may seem as though it leads to a higher mortality again…that’s for you all to determine).  I only point this out to show there has been a change in management for these patients since most of this data was published.

To further bash nitro, in a relatively recent review article on nitroglycerin for acute decompensated heart failure, the authors flatly conclude that there is currently not enough evidence to recommend nitro as a standard treatment.     

My bottom line for judicious nitro administration:

Nitro has NEVER been shown to have a mortality benefit in ADHF, weight risk vs benefit     

Patients presenting with concomitant ischemia take precedence  

Couple it with a good dose of diuretic

Reserve it for patients requiring BiPAP or intubation  

Reserve it for patients with an SBP of at least 120    

Start at a LOW dose and titrate up every 5-10 minutes to max of 200 mcg/min      

Avoid hypotension! Hypotensive events = mortality in these patients. BiPAP will drop their pressure. Give them a minute to have those million molecules of oxygen bombard their lungs. Their work of breathing will decrease, their endogenous catecholamine surge will subside, their pressure will go down.

Give the nurse clear instructions for titrations and explain the goals of therapy  


Titrate the drip with the nurse for a while to see how the patient is responding to therapy

Get weird with it and request some nitroprusside or nesiritide!  Increase your drug repertoire, increase your knowledge, increase your comfort level  


Feel free to approach me with any questions or concerns about the medication management of heart failure patients.  I can also get you my references if you want your mind blown.    

Forget what ya’ heard.  Nitro may not be the saving grace you may think it is.

CK here- you may be thinking, What? Nesiritide kills people and NTG is awesome, everyone knows that. just look at http://crashingpatient.com/medical-surgical/cardiology/heart-failure-acute-pulmonary-edema.htm/

Or at least nesiritide doesn't work [see  http://www.thepharmacyconnection.com/cardiology/2011/07/07/is-this-nesiritides-last-call-for-acute-heart-failure-ascend-hf-published/ or read the ASCEND-HF trial in NEJM 2011].

Neal, however, has a well reasoned reply:

NTG:  We do not use it as they do in these studies.  I’ve never seen high-dose boluses of NTG in our ER.  I’m not sure how that blog crashingpatient gets away with using strong wording like “very effective” when referencing a trial of 9 patients.  I have been noticing a regurgitation of Scott Weingart anecdotes that are only based on a couple of his patients and his expert opinion…the same level of evidence he jokingly calls “GOBSAT (Good ole boys sitting around a table).”  
These studies have incredibly low numbers, most are non-randomized, convenience sampling, open-label, violate their pre-specified protocols, and don’t reflect current practice (i.e. non-invasive ventilation).
How is no one bringing any of this up?  There is clear bias towards utilizing NTG.  My argument in the post is that this bias is at least partially due to unfamiliarity with other medications.
Nesiritide:  I didn’t mean for it to seem that nesiritide is a clear winner over NTG.  I agree the data is not great.
Nitroprusside: Where are the criticisms for this medication in the setting of ADHF?  I personally believe that more people are silent on this because there is some data advocating the use but got overshadowed by ease of NTG, thus falling to the wayside.  This is a great candidate to replace NTG if there was no more NTG.
The whole point of this is to have critical responses.  The culture is to give NTG.  The levels of recommendation were put in there to show that evidence is sparse and most are in context of diuretic administration (people love to bash diuretics, but fail to admit there is just as big a void of data for nitrates).  I personally don’t care how much NTG gets used when we have it, whether the patient is a good candidate or not (just as long as they don’t get symptomatically hypotensive).  What I advocate is the responsible use of a dwindling product.

Antibiotics and COPD

Clinical Scenario and PICO question

Buds Ambulance brings a 68 yo male into room 4A with a chief complaint of 3 days of gradually progressive shortness of breath, now so bad that he had to quit smoking. His cough has gotten worse with more sputum, which he says is green and yellow.  He has wheezing and chest tightness at home, typical for his usual COPD exacerbation.  He doesn’t know if he had a fever, but he has had some chills. 
ROS: negative for CP, abdominal pain, N/V, leg pain or leg swelling, documented fevers.  
Meds: Lotrel (amlodipine/benazapril),  Combivent MDI (albuterol/ipratropium), Flovent MDI (fluticasone)
Social Hx:  stopped smoking 2 days ago
PE:  142/82, 90, 26, 37.8, O2 Sat RA 90%
Dyspneic, speaking in short sentences.
HEENT:  neg
Lungs:  decreased breath sounds with inspiratory and expiratory wheezing bilaterally.
Cor:  RRR, no M/R/G
Abdomen: soft, NT, no mass or HSM
Extrem:  no C/C/E, nontender, no cords, has normal pulses bilaterally
ECG:  NSR, diffuse flattened T waves, no acute ST changes
CXR:  no infiltrate or CHF, has flattened diaphragms
Labs:  Normal BMP and negative troponin, WBC 10 K, Hgb 13, Platelets 300 K.
After Albuterol 10 mg/Ipratropium 0.5 mg, prednisone 60 mg po, and BIPAP, your patient is appearing more comfortable.  You are ready to call the next-up for admission and move on to the patient with non-specific CP in room 5, when your attending asks you about antibiotics.  There is no pneumonia on CXR, but the patient does appear to have some infectious symptoms…
P:  Moderate to severe COPD exacerbation, CXR without infiltrate but increased, purulent sputum
I:  Antibiotics + Usual care 
C:  Usual care
O:  Treatment Failure, Mortality, Antibiotic complications (allergic reaction, diarrhea)


The idea for this JC sprung out of the perceived clinical variability in our department in the treatment of COPD exacerbations with antibiotics.  As background, the 2004 ATS guidelines state that antibiotics may be initiated for outpatient or inpatient COPD exacerbations in patients with a change in their sputum characteristics (purulence and/or volume) and should be given if the patient is admitted to the ICU.  The 2010 GOLD (Global Initiative for Chronic Obstructive Lung Disease-joint project of NHLBI and WHO) guidelines recommend antibiotics for COPD exacerbations in patients with increased sputum purulence + increased sputum volume + increased dyspnea, or increased sputum purulence + increased volume or dyspnea, or intubated patients.


What is the evidence behind these expert recommendations?  As discussed below, it’s pretty modest.  Article #1 is the only recent RCT on the topic, Article #2 is a large retrospective cohort study evaluating outcomes in patients treated early with antibiotics, and Article #3 is a Cochrane review of all RCTs on the subject through 2005.

A historical word:  the background article by Anthonisen is still frequently referenced.  This study derived the most widely cited scale for grading the severity of acute COPD exacerbations, and combines pertinent symptoms into three categories:

Type 1 exacerbation:  All of the following symptoms are present: increased dyspnea, sputum volume, and sputum purulence.

Type 2 exacerbation:  Two Type 1 symptoms are present.

Type 3 exacerbation:  At least one Type 1 symptom is present plus upper respiratory tract infection symptoms or fever or increased wheeze or cough or increased resp. rate or heart rate.

In Anthonisen’s study, patients with Type 1 or Type 2 exacerbations had higher rates of clinical success and fewer episodes of deterioration.  Ok, it’s 24 years old, and a lot has changed in COPD management since then (BIPAP anyone?), but it’s good to be familiar with where it all started.


#1.  Daniels JMA, Snijders D, de Graaff CS et al.  Antibiotics in Addition to Systemic Corticosteroids for Acute Exacerbations of COPD. Am J Respir Crit Care Med 2010;181:150-157.

This RCT from the Netherlands compared outcomes in 265 COPD exacerbations (defined as increased dyspnea + increased sputum volume or purulence) treated with either doxy + steroids or placebo + steroids in hospital.   Patients with pneumonia were excluded.  The primary outcome measure was clinical response on Day 30.  Secondary outcomes included clinical success on Day 10, clinical cure on Days 10 and 30, lung function, CRP, symptoms, microbiological response and antibiotic treatment for lack of efficacy.  There was no difference in the primary outcome (61% clinical success in doxy group at Day 30, 53% in placebo group).  The authors stressed the positive results of the secondary outcome, clinical success at Day 10 (80% doxy, 69% placebo).  Clinical cure at Day 10 also was significantly higher in the doxy group.  Lung function results did not differ between the 2 groups, and symptom scores on a non-validated scale favored the doxy group at Day 10 but not at Day 30.  Bacteriological response was higher in the doxy group, but the clinical importance of this result is unknown, as colonization versus infection is difficult to determine, and persistent colonization even after appropriate antibiotic treatment is well described.  Serious adverse events occurred in 11 patients (9%) of the doxy group, including 7 deaths, as compared to 7 patients (5%) and 3 deaths in the placebo group.

Issues/Discussion:  As Christine brought up, Day 30 outcome is a strange choice.  We expect improvement earlier, and as Erin discussed, 10 day improvement can be very important with regards to improved quality of life, and also to help break the cycle of recurrent exacerbations.  Michelle mentioned the large number of exclusion criteria, limiting the external validity of the study (can we apply the results to our patients?).  Erik pointed out that the authors left out the number of eligible patients sampled (top of the fishbone diagram).  This is a recurrent theme, and increases the likelihood of a Type I (false positive) error, and therefore limits the internal validity of the study.  Erik also brought up the doubled mortality rate in the doxy group, which is not discussed further in the paper.


#2.  Rothberg MB, Pekow PS, Lahti M, et al.  Antibiotic Therapy and Treatment Failure in Patients Hospitalized for Acute Exacerbations of COPD. JAMA 2010;303:2035-2042.

This retrospective cohort study compared outcomes of hospitalized patients with COPD exacerbations but without pneumonia who either received antibiotics during the first two days of hospitalization or received late or no antibiotics.  The primary outcome was a composite measure of treatment failure that included mechanical ventilation, mortality, or readmission for COPD within 30 days.  Secondary outcomes included hospital cost and LOS and antibiotic associated adverse reactions.  Over the study period, 84,621 admissions from 413 acute care centers were included.  The risk of treatment failure was lower in the antibiotic treated patients (odds ratio 0.87; 95% CI, 0.82-0.92).  Each component of the composite primary endpoint was statistically lower in the group treated with antibiotics.  Patients treated with antibiotics had a higher rate of readmission for Clostridium difficile than those not treated with antibiotics (0.19%; 95% CI, 0.187%-0.193% versus 0.09%; 95% CI, 0.086%-0.094%).  

Issues/Discussion:  With retrospective studies it’s impossible to determine why certain patients did/did not receive treatment (antibiotics).  Although the authors attempted to correct for this using multivariable adjustments, the study remains vulnerable to selection bias.  As Matt discussed, the very large sample size allows the authors to look at rare outcomes (e.g. mortality) but with very large numbers, p values may be “significant” without there also being clinical significance (statistical versus clinical significance).   The readmission rate for C. difficile was low in both groups, but as Ben pointed out, the increasing rates of quinolone use lead to more C. difficile in the future.  Also, the patients treated with antibiotics were healthier overall, and this favors the antibiotic group.  Ben also calculated some numbers needed to treat.  Remember, the NNT = 1/ARR, and for the composite outcome, the NNT is 50.  For each of the components, the NTT is >100, so although the outcomes favor antibiotics, the treatment effect is modest.  Finally, Chintan made the important point that the study design will miss many patients with complications.  To be enrolled, patients needed a principal diagnosis of COPD or respiratory failure with COPD.  If a patient then had an MI, MI would likely be the principal ICD-9 code, and the patient would have fallen out of this study.


#3.  Ram FSF, Rodriguez-Roisin R, Granados-Navarrete A et al.  Antibiotics for exacerbations of COPD.  Cochrane Database of Systematic Reviews 2006, Issue 2. Art No.:  CD004403.

This Cochrane review includes all RCTs comparing antibiotics to placebo in patients with acute COPD exacerbations since 2005.  Eleven trials with 917 patients were included.  Their conclusion:  in COPD exacerbations with increased cough and sputum purulence, antibiotics significantly reduce the risk of short-term mortality (NNT 8; 95% CI 6-17) and treatment failure (NNT 3; 95% CI 3-5) with an increase in the risk of diarrhea (NNH 20; 95% CI 10-100) compared to placebo.  The authors admit that the results should be interpreted with caution due to differences in patient selection, antibiotic choice, the small number of trials, and the lack of controls for other interventions (steroids, BIPAP).  They acknowledge the growing resistance rates to common antibiotics and recommend limiting antibiotics to patients with COPD exacerbations and infectious symptoms who are moderately or severely ill.

Issues/Discussion:  As Jess discussed, there are huge variations in the definitions of COPD, the patient populations included, and there is no standard definition of “usual care”.  Gromis commented that the trials are in general old (only one published in the last 10 years), limiting the ability to generalize to current care of patients with COPD.  In addition, reviews like this suffer from publication bias:  studies demonstrating a positive treatment effect are more likely to be published than negative studies.


So, what’s our take home?  The data aren’t great, but modestly support antibiotics in patients with COPD exacerbations and infectious symptoms (in the absence of pneumonia).  Consensus of the faculty members in the room is to give antibiotics to patients with infectious symptoms.  Some give them to all COPD patients being admitted, and everyone agreed that antibiotics are indicated if the gestalt is that the patient looks “sick”.  The decision may be more difficult if the patient was just recently admitted or just recently finished a course of antibiotics.  Erik and Dan struck the cautionary note that given the doubled mortality in the first study for the antibiotic group, we may not be that far from clinical equipoise, and although they both prescribe a lot of antibiotics for these patients, we may also be doing harm (C. diff, etc).  As Dan pointed out, it’s ironic that in our last JC, we pushed hard against prescribing unnecessary antibiotics for AOM, and here we have a much more liberal prescribing policy.  Both conditions have reasonably high placebo success rates, but there are higher clinical consequences of treatment failure with COPD.  Final thought; if you’re giving antibiotics, think macrolides.  They appear to have anti-inflammatory effects at least partly independent of their anti-microbial effects, and are excellent agents against common respiratory pathogens.


Background Article

Antibiotic therapy in exacerbations of chronic obstructive pulmonary diseas. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Ann Intern Med. 1987 Feb;106(2):196-204.

Reversal of Warfarin

Our question was:  given a generally healthy asymptomatic patient on warfarin for afib who is sent to the ED because of an elevated INR of 8 but who has heme + brown stool and a Hgb of 11, what is the appropriate intervention (hold warfarin only, or also treat with vitamin k, and if so, at what dose/route)?  What are the risks of bleeding, and what are the thrombotic risks?

First, as a reminder, our patient has a CHADS score of 1.  This represents an annual stroke risk of 2.8% for patients with afib (see below), so warfarin treatment is reasonable.   Unfortunately, even in warfarin clinics, INRs are outside the therapeutic range one third to one half of the time.  It’s well accepted that bleeding risk increases with increasing INR, especially when INR >4.  What is our patient’s risk of bleeding?   

Garcia DA, Regan S, Crowther M, Hylek EM. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol. Feb 21 2006; 47:804-808

evaluated a cohort of 979 patients with a first episode of INR >5.  During 30 day followup, 0.96% of patients with an INR >5<9 experienced major hemorrhage.  When the INR >/= to 9, the risk of bleeding increased to 9.5%.  Only 9% of patients in this study received vitamin k (mostly 2.5 mg or less).  So, a good place to start:  there’s about a 1% 30 day risk of major bleeding when your INR >5 <9.  There were no ICHs in this study.  In the Aiyagari background article on ICH/warfarin, a range of 0.3-0.6% per year risk of ICH while on warfarin is quoted, but as Harwood pointed out, the risk of ICH skyrockets in the elderly.

So, how should we protect our patient?  The meta-analysis,

Dezee KJ, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. Feb 27 2006; 166:391-397

evaluated all of the RCTs and prospective nonrandomized trials using vitamin K to treat patients without major hemorrhage with an INR >4 on oral anticoagulants, from 1985-2004.  Unfortunately, as they admit, the quality of studies available was fair to poor, leading to a concern of “garbage in, garbage out.”  There were a few limited conclusions.  Subcutaneous vitamin K is no better than placebo.  Just don’t use it (and this is also part of the 2008 ACCP guidelines).  Oral and IV vitamin K worked about equally as well in this meta-analysis, but with the risks of anaphylactoid reactions with IV vitamin K, you should choose oral if the patient isn’t having major bleeding.  Most (about 80%) patients with INR <10 who receive oral vitamin K (2.5 mg or less) will have an INR < 4 in 24 hours.  That’s fine, but does giving vitamin K prevent bleeding?  Does giving vitamin K cause an increased risk of thrombosis? Sorry, but no answers from this meta-analysis due to the fair/poor quality of the included studies.

So, our third article came out in 2009.  It’s a large study of over 700 non-bleeding patients with INRs of 4.5 to 10, trying to look whether or not giving low dose vitamin K (1.25 mg) decreases bleeding risk.

Crowther MA, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med. Mar 3 2009; 150:293-300  

At 90 days, this study demonstrated no significant difference in the rates of bleeding between patients receiving 1.25 mg vitamin K vs. those receiving placebo.  The study was under-powered to detect a difference in major bleeds, although interestingly, more major bleeds occurred in the vitamin K group (likely chance, but the major bleeds all happened >30 days out-could there be issues with re-starting warfarin and maintaining a therapeutic INR after receiving vitamin K?).  Although death and thromboembolism were rare and rates were balanced between the 2 groups, these were secondary outcomes and no firm conclusions are possible.  Erik Kulstad made several important points about the methodology:  there are issues of external validity (ability to apply study conclusions to your own patients):  patients enrolled in studies are different-they are compliant, in general healthier, and in this case had amazing followup with multiple phone calls, likely identifying problems/bleeding more frequently than in an unselected population.  Also, we are missing an explanation of who and how many patients were not included in the study-who are the ineligible and missed patients?

So, coming back to our patient….after much discussion, we took votes on 2 different patients:  first, our PICO patient, but without heme positive stools.  Everyone in the room agreed to send him home, and all except one would not give him vitamin K.  When the patient had heme + stools (occult GI bleed, no melena, and stable/asymptomatic), still most would send him home, although now many would given low dose vitamin K (1-2.5 mg, orally).  Again, as Harwood pointed out, you only need to change one variable to dramatically change risk and outcome and disposition (old, or melena, or poor social situation, or INR 11).  Still, we do see a ton of patients like our PICO guy, and I believe this JC supports being more comfortable with doing less than many us (me included) may have done in the past.  Interestingly, in the most recent ACCP guidelines from 2008, although the table looks similar to 2004, the doses of vitamin K recommended are half of the 2004 recs for patients without significant bleeding (both INR 5-9, and INR >9). 

Last point:  we chose the PICO patient deliberately:  the heme + stools and hgb 11 means that he isn’t really exactly  like any of the patients in our studies.  There is no “right answer” on how to treat him. Involving the patient in his medical decisions is the “third circle” of EBM (evidence, clinical experience, and patient values).  Maybe he is really afraid of a thrombotic stroke or MI.  Maybe he doesn’t have insurance and isn’t going to get his INR rechecked tomorrow.  You get the idea.



CHADS score for background:


 C   Congestive heart failure 1
 H  Hypertension (or treated hypertension) 1
 A  Age >75 years 1
 D  Diabetes 1
 S2  Prior Stroke or TIA 2
Annual Stroke Risk
CHADS2 Score  Stroke Risk %      95% CI      
0 1.9  1.2–3.0
1 2.8  2.0–3.8
2 4.0  3.1–5.1
3 5.9  4.6–7.3
4 8.5  6.3–11.1
5 12.5  8.2–17.5
6 18.2 10.5–27.4