My name is Arzo Hamidi, and I'm a medical ICU pharmacist at Rush University Medical Center. Today's talk is entitled Putting Lipstick on the Prophylaxis Pig. I have no disclosures. The objectives are to critique conventional dosing for venous thromboembolism, or VTE prophylaxis, to review updated indications for stress ulcer prophylaxis, or SUP, and to evaluate the influence of animal nutrition on SUP indication. To begin with the VTE prophylaxis section, let's review some recent literature published on DVT prophylaxis. The CHESS guidelines from 2012 suggest that low molecular weight heparin, or unfractionated heparin, is preferred over no prophylaxis. A Cochrane review in 2014 suggests that LMWH is preferred over UFH due to reduced risk of DVTs and bleeding. Meta-analysis from 2015 suggests that LMWH has reduced risk of DVT compared to UFH, and there is no difference in rates of PE or bleeding. And lastly, the American Society of Hematology Guidelines last update in 2018 suggests that LMWH should be preferred over UFH. What we see from this literature is that LMWH is preferred over UFH for DVT prophylaxis in medical patients in many situations. Though some institutions may use daltaparin, I'll be reviewing the use of anoxaparin specifically. The typical dose is 40 mg once a day, and the widely accepted range for anti-factor 10A levels for prophylaxis is between 0.2 and 0.4 IU per mL. The first of the three studies we'll discuss had patients who weighed 45 kg or less and received 40 mg once a day. They didn't see any rates of VTE, but did have major bleeding in about 7% of their patients. The second study had 210 patients who weighed 45 kg or less, and they received 30 mg once a day, 30 mg twice a day, or 40 mg once a day. This study also didn't report any rates of VTE, but the rates of major bleeding varied between 13% and 22% of these groups. Lastly, the third trial had 56 patients who weighed 55 kg or less and received standard dosing of 40 mg once a day. The results were re-stratified based on the patient's weight categories, and you'll see that in all of the groups, the patients had a therapeutic anti-factor 10A level. Unfortunately, this study didn't report VTE or major bleeding rates. On the other end of the weight spectrum, let's review the use of prophylactic anoxaparin in obesity. The first of the four studies was a pharmacokinetic study with 28 patients who had a BMI greater than 35. They received anoxaparin 0.5 mg per kg per day, and anti-factor 10A levels in this group were appropriately in the prophylactic range. The second study with 31 patients with a BMI greater than 40 received either 0.5 or 0.4 mg per kg per day, or the standard dosing of 40 mg once a day. The anti-factor 10A levels were less than 0.2 in 13% and 36% of the 0.5 and 0.4 mg per kg per day, respectively, and as high as 82% in the group receiving 40 mg once a day. The third study had 91 patients with a BMI greater than 30, and they received either 60 or 40 mg once a day. In both of these groups, their anti-factor 10A levels were appropriately in the prophylactic range. The fourth study had 80 patients with a BMI greater than 40, and they received either 0.5 mg per kg per day or 40 mg twice a day. Both of these groups had anti-factor 10A levels that were in the prophylactic range. This study was the only one of these four that actually reported rates of VTE in bleeding, and actually neither group had any. It would be nice to have seen efficacy and safety data in addition to the anti-factor 10A levels in this patient population, so maybe we'll see that with future studies. To summarize dosing recommendations for anoxaparin, 40 mg once a day is appropriate for most patients. For patients with a low body weight as 45 kg or less, I'd recommend 30 mg once a day or an alternative agent altogether. For patients who are obese with a BMI greater than 40, I'd recommend 40 mg twice a day or a weight base of 0.5 mg per kg per day divided into one or two doses. It's also important to remember that renal dose adjustments are required in all of these scenarios. For patients who can't tolerate low molecular weight heparins due to a renal function or other reasons can use unfractionated heparins instead for DVT prophylaxis. On this slide we'll go over three studies that compared 5,000 units twice a day to three times a day for this indication. The first study had over 4,000 patients and the incident rates of VTE were non-significantly different between the two groups. The rates of major bleeding were also not different. The second study with almost 800 patients did not have any significant differences in VTE or major or non-major bleeding rates. The third study with over 30,000 patients specifically in the ICU also had no significantly different VTE rates or major bleeding rates. With this we see that in different patient populations there are no significant differences overall in VTE or major bleeding rates. We have reviewed a few studies looking at 5,000 units of heparin three times a day compared to twice a day. Though we didn't see differences in terms of safety or efficacy there are some additional considerations in giving the medication one additional time per day. That includes compromising sleep in case that administration time is in the middle of the night, patient discomfort or pain from a sub-Q administration, the nursing resources into going into getting an additional medication, preparing that into the syringe and administering it, and then lastly the cost to the pharmacy and the increased use of a medication and then also the patient in receiving something an additional time per day. To summarize conventional dosing for DVT prophylaxis we learned that dose reductions or increases are necessary for anoxaparin in extremes of body weight. We also learned that unfractionated heparin VID is equal to TID but there are some additional decreased costs, use of resources, and patient discomfort in administering it twice a day. And then lastly the literature doesn't support routinely checking anti-factor TINAs as they don't correlate to the same clinical significance in terms of VTE incidence or bleeding rates. Moving on to our next topic we'll discuss stress ulcer prophylaxis. Previously the sub-guylines that we often referred to were developed by ASHP in 1999. If a patient had one major risk factor or if they had more than two minor risk factors they would be indicated for sub. Those risk factors are listed here on the slide. In 2020 a new set of guylines came out in DMJ. These risk factors were stratified into highest, high, and moderate and then other minor risk factors. If a patient had highest risk or high risk or if they had two or more moderate risk factors they would be indicated for stress ulcer prophylaxis. Just to review what these risk factors are defined as, chronic liver disease refers to portal hypertension, cirrhosis, variceal bleeding, and or hepatic encephalopathy. Coagulopathy is defined as platelets less than 50,000 or an INR greater than 1.5. And shock is defined as the use of vasopressors or inotropes, systolic blood pressure less than 90, a MAP less than 70, or a lactate greater than 4. In the last five years several studies have come out comparing the use of pantograzole 40 mg IV to placebo for stress ulcer prophylaxis. These studies had varying sample sizes anywhere from 91 to over 3,000 patients and were well-designed prospective multi-center and often international studies of mixed ICU patients. You'll see that the outcomes reported for regards to bleeding and mortality were not significantly different in almost all the studies. In the last trial listed, sub-ICU, you'll see that clinically significant bleeding was different and higher for those receiving placebos compared to the PPI, but all the other outcomes reported were not significantly different among these trials. Makes you question, is something else going on that shows that there's no difference in a pharmacological agent used for stress ulcer prophylaxis? To explore this a little bit further, this is a meta-analysis in almost 900 ICU patients who were receiving enteral nutrition comparing sub to placebo. In terms of over-bleeding, clinically significant bleeding, mortality, and C. difficile infections, there is no statistically significant increase in those who received sub and enteral nutrition as compared to enteral nutrition alone. However, in terms of rates of VAP, there was a statistically significant increase in those who received both sub and enteral nutrition. To bring back the studies about Pantoprazole 40 mg IV to placebo, let's also review how much enteral nutrition these patients received. You'll see anywhere between 80% and 100% of patients were fed within a short amount of time. This suggests that enteral nutrition may have played a protective role and that may be the reason why we didn't see statistically significant differences between these groups comparing placebo to a PPI. The studies we reviewed look specifically at the use of Pantoprazole 40 mg IV for stress ulcer prophylaxis. However, there has been a date for years, maybe even decades, comparing PPIs to H2RAs for sub. This was a study published in 2021 looking at the effectiveness and safety of PPIs as compared to H2RAs. It was a retrospective single-center study of over 3,000 patients who were in the ICU receiving mechanical ventilation for more than 24 hours who were started on sub within 48 hours. For the primary outcome, they evaluated hospital mortality, which was significantly higher in the PPI group. For safety outcomes, they compared rates of C. difficile infections, which were no different between the two groups, ventilator-associated pneumonia, which was also no different, and clinically significant bleeding, which was higher in the PPI group. Important limitations to mention include the overall low incidence of GI bleed, which may impact these results due to the low occurrence of the primary event, and treatment bias since the agents were chosen based on provider discretion in this retrospective study. In conclusion, though, they found that there was increased hospital mortality in clinically significant bleeding with PPIs as compared to H2RAs. A second study to highlight comparing PPIs to H2RAs was the PEPTIC study published in 2020. It was a multi-center, randomized, open-label, cluster-crossover international study with over 26,000 patients. The primary endpoint of this study was 90-day mortality, which was higher in the PPI group but it was found to be not significant. The safety rates included C. difficile infection, which were no different, ventilator-associated pneumonia, which were also not different, and clinically significant bleeding, which was higher in the H2RA group. The important limitation to mention is just the low adherence rates to the assigned agent in this crossover study. And lastly, the authors concluded that there was no difference in mortality in PPIs versus H2RAs in this study. As we continue to try and answer the question of which agents are preferred, this was a meta-analysis published in 2020 comparing PPIs to H2RAs. This figure shows that there is benefit with PPIs in the reduction of clinically significant bleeding, but there is still a benefit seen with H2RAs. As far as those same safety outcomes that we were evaluating, they found that overall, C. difficile infections are rare, so it's hard to say which one may increase the rates of it. And both PPIs and H2RAs are associated with increasing risk of ventilator-associated pneumonia compared to placebo, and again, they couldn't conclude which one has a higher rate of incidence. To summarize our review of stress ulcer prophylaxis, it's important to consider a patient's risk factors and to initiate SEP within 24 to 48 hours. Secondly, if a patient's not receiving enterotrition, then consider either a PPI or an H2RA, but always consider an oral agent if possible. And then lastly, in remembering that less is more, discontinue the agent when it's no longer indicated. I'd like to thank you for your time, and if you have any questions, please reach out to me and I'd love to discuss this further with you.

Arzo Hamidi

medical ICU pharmacist

dosing recommendations

venous thromboembolism prophylaxis

stress ulcer prophylaxis