More on Zetia: IMPROVE-IT Study

I'm sure you all have been seeing the publicity of the IMPROVE-IT study showing benefit of zetia added to zocor follow cardiovascular events (secondary prevention). I've not been a fan of zetia, so have approached the article with some skepticism, but hopefully what I share below is objective enough. 
Some points:

  •  secondary prevention study
  • zocor study, with 26% on zocor 80 mg (no longer recommended)
  • no difference in all cause mortality nor any mortality difference in stroke or MI. FYI: zocor had a nnt of 30 over 5 years for all cause mortality benefit and 31 for coronary mortality (over 5 years)
  • benefit found in stroke with a number needed to treat of 186 for 7 years to prevent 1 stroke (if just ischemic stroke, nnt is better, but higher hemorrhagic strokes in zetia with zocor arm). FYI: The NNT from sparcl for Lipitor to prevent one cva in 5 years was 45.
  • Benefit for non-fatal MI: nnt of 66 (7 years again)
  • benefits in revascularlization but not in hospitalization for unstable angina. FYI: Lipitor 80 mg had nnt of 38 for revascularlization over 16 weeks if given within 4 days of revascularlization. 

Some thoughts:

  • I'm always bothered by the lack of mortality benefit, but the assumption would be that preventing strokes and MI's will eventually lead to mortality benefit. 
  • the comparison was not with high potency statins which have stronger data (Lipitor). Of course, the question is whether zetia would have helped improve the Lipitor data. 
     

My take away:

I'll add zetia for:

  • those patients who can not tolerate high dose, high potency statin.
  • For patients who are the disaster vasculopath.

For patients who are on high dose, high potency statin, I do not feel there is sufficient data. At best, it may prevent some events but no mortality benefit at 7 years. 


**please note, several of the NNTs were my own calculations and I could have certainly made a few errors!

Zetia vs Statins: NNT

Came across this today concerning adding ezetimibe to a statin for secondary prevention (stroke and heart attack). I must admit, I am not a fan of ezetimibe and approached this article looking to tear it apart… With this in mind, I found the results interesting. To prevent 1 event (stroke or heart attack), you would need to treat (Zocor + Zetia) 50 people for 7 years. There wasn’t any mortality benefit. I need to review the article, but event his amount of information raised a question on what the NNT was for statins. I immediately went to a great website called theNNT.com that list all of the NNT for different interventions (awesome site) and checked for statins. Here is what I found:

  • Statins for secondary prevention (start after an event):
    • Mortality benefit: treat 83 people for 5 years to prevent 1 death
    • 39 people for 5 years to prevent 1 heart attack
    • 125 people for 5 years to prevent on CVA
  • Statin Data for primary prevention:
    • Mortality: none
    • Heart attack: need to treat 60 people for 5 years to prevent 1 heart attack
    • Stroke: need to treat 268 people for 5 years to prevent one stroke.

Based on this, where does ezetimibe fall for you all? 

IMPROVE-IT: Modest Clinical Benefit from Ezetimibe

By Larry Husten

Edited by David G. Fairchild, MD, MPH, and Jaye Elizabeth Hefner, MD

Adding ezetimibe to statin therapy in patients with an acute coronary event is associated with a small reduction in adverse cardiovascular outcomes, according to results of the IMPROVE-IT study presented Monday at the American Heart Association meeting.

Roughly 18,000 high-risk patients were randomized after an acute coronary event to either ezetimibe or placebo on top of a statin. Patients had LDL levels of 50-125 mg/dL, or 50-100 mg/dL if on a prior cholesterol drug. 

After an average of 6 years' follow-up, primary endpoint events — CV death, MI, hospitalization for unstable angina, coronary revascularization >1 month after randomization, or stroke — occurred in 35% of the placebo group versus 33% of the ezetimibe group, a 6.4% reduction in risk. Researchers calculated that 50 patients would need to be treated for 7 years to prevent one event. There were no differences between the groups in overall deaths, coronary deaths, or cardiovascular deaths, but there were significant risk reductions in MI (13%), stroke (14%), and ischemic stroke (21%). Diabetics had a larger benefit than nondiabetics.

At the AHA press conference, Neil Stone, the chairman of the AHA/ACC cardiovascular guidelines committee, said that ezetimibe should now be viewed as a proven therapy. The results, he said, expand the options for additional proven lipid-lowering therapies that have been shown to add incremental benefit.

AHA news release (Free)

Background: Physician's First Watch coverage of earlier ezetimibe study(Free)

Systolic Heart Failure Trials: Fun Look at NNT

With the twins off at the grandparents, John sleeping in, and Pete busy running around in the backyard, I had the very rare joy of sitting on my deck reading on my iPad. One of the articles I came across had a very interesting graph (shown below) comparing the NNT for the different systolic heart failure trials. Unfortunately, I could not remember what all the different trials and was especially curious about the MADIT-CRT trial. Thankfully, Journal Club (which I spoke about in a prior blog post), came to the rescue. Just for fun, here are the different trials with NNT. 

  • Carvedilol: I'm not sure which trial the graph is refering to, so I just pulled the major carvedilol trials assuming the table is pulling the subset from the US with EF <35% (for comparison's sake)
    • COPERNICUS: Carvedilol vs placebo for patients with Class III and IV HF with EF <25%. Incredibly, the NNT for 1 year mortality was 15!! Wow, place 15 people with an EF <25% (and NYHC of III or IV) on carvedilol and you will prevent one death. That is impressive!
    • Another trial looking at Carvedilol was the COMET Trial which compared carvedilol to metoprolol tartate (the short acting, twice a day, metoprolol). There were a couple of things that were a bit unfair about the trial (metoprolol succinate was the form shown to have benefit for HF mortality (MERIT-HF) and the dosing for metoprolol tartate was a bit lower), but carvedilol did beat metoprolol tartate when it comes to mortality. The take away on this is that carvedilol really should be our drug of choice, and if we use metoprolol, we must use metoprolol succinate. 
  • SOLVD-T: Study looked at enalapril vs placebo in patients with Class II-IV HF with an EF 35% or less. "The authors esitmate that treating 1,000 CHF patients with enalapril for approimately 3 years would prevent 350 hospitalizations and 50 premature deaths". 
  • AHEFT: This was the really cool study that showed isosobide dinitrate pulus hydralazine reduced mortality and hospitalization in Black patients with a NYHA of III-IV and EF less than 35% (or <45% if certain echo findings). NNT: 25
  • MADIT-CRT: All of the MADIT-CRT trials are looking at ICD's, either with synchronization or alone following an MI and poor EF. 
    • MADIT-CRT-II: ICD following an MI and EF 30% or less. NNT: 18. By the way, there was a follow-up study which showed ICD reduced death for EF 35% or below whether post-MI or not Post-MI, but the data was not as impressive.
    • MADIT-CRT: ICD with cardiac resynchronization for patients with wide QRS (>130 msec) and EF 35% or lower. For the composit outcome of non-fatal HF events and all cause mortality, the NNT was impressive (12). Clearly, taking the non-fatal HF events out of the picture, the NNT is far less impressive (see chart). There have been follow-up studies on this one. The take away for me: morbidity certainly seems improved in this population, but I am not as convinced on the cost-effectiveness as it relates to mortality. I shoudl state though, this is not an area of medicine I have spent nearly enough time on reading and really shouldn't have a strong opinion.
  • SHIFT: This was a new one for me, requiring a bit more research. The SHIFT trial looked at ivabradine, a seletive sinus node inhibitor, in patients with an EF 35% or less and a HR of 70 or over. The trial showed an overall reduction in the combined outcome of hospitalization or death, but according to UpToDate, the reduction was more prominent in the readmissions than death. 
  • EMPHASIS: Looked at eplerenone (mineralcorticoid receptor inhibitor similar to spironlactone but without all of the enodocrine side effects such as gynecomastia breast pain, sexual dysfunction) in patients with NYHA of II or worse and EF 35% or below. In the combined outcome of death or hospitalization for HF, the NNT was 19 and for death was 51. Pretty impressive!
  • PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor): this is the study which I was reading this morning and started it all! This is a look at new drug class, angiotensin receptor-neprilysin inhibitor, in patients with EF 35% or worse and NYHA class II-IV. Very surprisingly, know what we know about ARBs vs ACE Inh, the novel agent was actually superior to the ACE Inh! Here is a paragraph from the accompany editorial that produced the below chart explaining the pathophysiology behind this new agent:

Why did LCZ696 succeed in improving outcomes so convincingly in this representative population of patients? Drugs that inhibit the renin–angiotensin–aldosterone system (RAAS) have been foundational to cardiovascular drug therapy for almost three decades. RAAS inhibitors moderate vasoconstriction, myocyte hypertrophy, and myocardial fibrosis, an effect that has translated into clinically meaningful improvements in functional status and survival. Natriuretic peptides, which include atrial natriuretic peptide, B-type natriuretic peptide, and urodilatin, are secreted by the heart, vasculature, kidney, and central nervous system in response to increased cardiac-wall stress and other stimuli. Natriuretic peptides have potent natriuretic and vasodilatory properties, inhibit the RAAS, reduce sympathetic drive, and have antiproliferative and antihypertrophic effects as well.6 Neprilysin inhibition results in an increased concentration of natriuretic peptides. Thus, the beneficial effects of RAAS inhibition are likely to be augmented by the enhancement of natriuretic peptide activity. 

Cool stuff! 

Please note: I do not know why the below chart does not seem to exactly match the NNTs I found... 

 

 

 

Interesting New Drug for MRSA Infections: Dalbavancin

Those of you who use Journal Watch (strongly recommend by the way), likely saw the small blurb on a new antibiotics, dalbavancin, receiving approval by the FDA for treatment of MRSA skin and soft tissue infections. In the blurb was a line which caught my attention:

The intravenous drug is given in two doses, 1 week apart.

Very interesting! I immediately thought of our patients who for a variety of reasons are not good candidates for home Vancomycin or PO zyvox (IV drug users who a PICC is not an option but zyvox is too expensive; elderly who you are hesitant to send home with IV antibiotics; patients with difficulty adhering to medications). With my interest peaked, I have quickly done some research into dalbavancin to see if there is a catch.

Mechanism of Action

Dalbavancin is a lipoglycoprotien, which is similar to the glycoproteins (vancomycin) but has an additonal lipophilic tail. One article called it a second generation glycoprotein antibiotic, which I kind of like because it helps me better understand where it stands in relationship to vancomycin. Its mechanism of action is similar to vancomycin: binds to C-terminal d-alanyl-d-alanine of the peptoglycan wall, stoppng cell wall synthesis. What is really cool is the lipophilic tail! While stopping the synthesis of the cell wall, the lipophilic tail inserts into the cell membrane, disrupting the cell membrane and contributing to cell death (very similar to daptomycin). It is this second part which may explain its increased in vitro activity for MRSA as compared to vancomycin. 

Activity and Spectrum

Dalbavancin is very potent, with MIC's that are very low and easily exceeded with a single dose. For MRSA, the MIC is 0.06 micrograms/L (compared to Vanc which is 1-2). Similar to Vancomycin though, the bacericidal level is higher than the MIC, and for dalbavancin it is 4 times the MIC. Luckily, dalbavancin will achieve levels over 30 micrograms/L for 1 week with a single dose, well above the bactericidal level (what a half life!). One study took a look at the concentration in "blister fluid", with dalbavancin concentration of 40. Pretty cool! Clearly it has a large volume of distribution.

Dalbavancin covers MRSA very well along with enterococcus, although it also can not cover VRE, raising quesitons about differences in the relationship of the cell wall and cell membrane between staph and enterococcus.

Addition coverage is as below:

Dalbavancin has variable activity against other pathogens, such as Lactobacillus spp. Its activity against corynebacteria is comparable with the activity of vancomycin. It also has potent activity against some Gram-positive anaerobes and fastidious aerobes including Actinomyces spp., Propionibacterium spp., andClostriudium spp. excluding Clostridium clostridioforme. Dalbavancin has minimal activity against Gram-negative bacteria, including Gram-negative anaerobic bacilli.

Safety

Dalbavancin appears pretty safe. It has the typical GI side effects, but there appears to be some bump in LFTs, especially those with prior liver disease. In looking at the numbers, this did not appear to be that significant, but because the FDA fast tracked the drug we do not have really large safety studies yet. I'm not sure if this will become an issue when the number of people exposed goes up from 1300 to 100,000, but we will see! For now, an author from mediscape recommended:

Some assessment of liver function, especially before the second dosing, is probably prudent, especially in patients with baseline liver function test abnormalities or history of liver disease.

My Conclusions

Dalbavancin seems like a pretty cool drug which could have some great clinical utility. There is certainly a need for this type of antibiotic, both for the ease of dosing and also for the growing rate of VISA (if MIC is over 2, Vanc really does not work well). My pause at this time is that I do not know how much it cost and I am also a bit anxious about the safety data. It appears very safe, but many meds look very safe initially and look very different after a much larger number of people have been exposed to it. I will take a wait and see approach, but I must admit, my trigger finger is a bit itchy for this one! 

 


References (links)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890846/

http://www.medscape.com/viewarticle/825348

http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=preview&language=en-US&anchor=H22#H22

http://www.jwatch.org/fw108872/2014/05/27/fda-approves-dalbavancin-treat-acute-bacterial-skin?query=pfw

http://www.jwatch.org/fw108673/2014/04/02/fda-advisers-recommend-approval-two-antibiotics

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398724.htm

And of course Wikipedia: http://en.wikipedia.org/wiki/Dalbavancin and http://en.wikipedia.org/wiki/Glycopeptide_antibiotic

My New Favorite App

I do not think it is any secret that I am a bit obsessed with Apple products and apps. Last year my wife showed me the breakdown of my expenses on my credit card (thanks American Express for making this so easy to do for my wife...), and the App Store section was scary! Unfortunately, showing me this data did not seem to have the effect my wife was hoping. Well, with all of this "research", I've come across a new "Must Have App": Journal Watch (link on iTunes)

Journal Watch is truly an incredible app that I have fallen in love with. As you can see below from the screenshots, Journal Club is a collection of all of the key articles in medicine over the past 20 years. Each article has a critical review, starting with a "Bottom Line" brief paragraph followed by everything you would expect from a critical review but in an easy to digest format. If there are national guidelines on the topic, the app will include these, broken down beautifully (see below the CVA Guidelines). 

AHA/ASA Stroke prevention for those with stroke or TIA (2011, adapted)[3]

  • Antiplatelets rather than anticoagulation for prophylaxis in patients with noncardioembolic ischemic stroke or TIA to reduce recurrent stroke and other CV events (class I, level A) with:
    • Aspirin 50-325 mg PO daily (class I, level A)
    • Aspirin 25 mg and extended-release dipyridamole 200 mg PO twice daily (class I, level B)
    • Clopidogrel 75 mg PO daily (class IIa, level B)
  • Dual therapy with aspirin and clopidogrel is not recommended as it increases risk of hemorrhage (class III, level A)
  • In patients with a stroke while on aspirin:
    • There is no evidence demonstrating that increasing the dose provides additional benefit (class IIb, level C)
    • Providers often consider alternative antiplatelet medications though no single or combination medication has been studied in this regard (class IIb, level C)

 

I really liked this app from the start, but what really pushed it into the "Must Have" category are the frequent updates. They continue to add articles, new and old 'classics'. I have incorporated the app into my nightly reading, often starting with the "Recent Updates" (Under More). 

Take a look and see if this is something that could work into your reading routine! Below are some screenshots highlighting a few features.

To Stress or Not to Stress?

One of the challenges I have on the inpatient service is the amount of stress tests we perform. Everyone knows the admission: some guy with atypical chest pain gets admitted, we don’t think it is cardiac but go ahead and stress them and send them home. The question I have is whether we should be stressing these patients. If a patient has chest pain that does not sound like it is cardiac in etiology, if they have a positive stress test does that suddenly mean the chest pain was cardiac in origin, or did we just happen to find an incidental finding. I suspect it is the latter. Then the question comes up, do we need to fix incidental findings?
Read More

Decrease III: Statin Fun!

We have been using statins to reduce perioperative cardiac events on the inpatient service for quite a while. The reality is, the data on its use in this situation is sparse. The best study is too small and didn’t actually reach statistical significance (although a trend towards benefit) (Lipitor with Vascular Surgery.pdf). It was also studied on patients undergoing vascular surgeries, not in grandpa’s hip replacement.
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When to Transfuse?

How often do you all hear one of us ask, “Well, at what Hg do you want to transfuse?”. It always becomes a game of “Guess What I am Thinking”. It often feels so arbitrary, that we could be playing the game of how many fingers I am holding up behind my back. What is the correct answer to this question? Is there a correct answer, or is it all ‘gut instinct’? Lets review some evidence.
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Early Goal Directed Therapy

Early goal directed therapy is a key concept for all of us to understand. Sepsis is something that we encounter on our service, and even more so when you rotate in the ICU. In this blog I will briefly review sepsis and early goal directed therapy, but both of these concepts are reviewed in much greater detail already (Sepsis Review Article, Early Goal Directed Therapy). Instead, I would like to go into detail on an update to early goal directed therapy, utilizing lactic acid clearance as opposed to central venous O2 sat as method to guide treatment (Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy: A Randomized Clinical Trial).
Read More

More Bad News for PPI's (and Indications for GI Prophylaxis)

Over the past year there has been significant negative press concerning PPI’s. This months Archives of Internal Medicine is nearly entirely dedicated to the problems with PPIs. This got my attention because PPI’s are often handed out like candy on our inpatient service. Why? Well, they are viewed as benign and they work. Anyone who suffers from GERD will attest to how great they are. They also give us something to give patients with atypical chest pain. Add in ‘GI prophylaxis’, and most of our patients end up on PPIs at some point. But who cares?
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Brand New Drug for Gout Called Colchicine

Great news on the battle with gout! A pharmaceutical company in Philadelphia PA is producing a new drug called Colcrys. Colcrys is the trade name for a drug called colchicine. Colchicine has recently been shown to reduce gouty attacks with just some side effects of diarrhea and vomiting. It has also been shown to work for prophylaxis. The FDA has approved it as a second line agent for gouty arthritis. I'm very excited about this new drug for those patients who are unable to take an NSAID. You all know how much a hate NSAIDS! Other than the diarrhea, the only other problem is the cost. Colcrys will cost $4.99 per pill. While this is pricey, especially considering the unapproved drug used for gout called "colchicine" cost only $0.09 per pill, at least this medication is FDA approved for the indication of gout! Of course, that old, cheap drug was not approved because no one had done the study needed for the FDA.
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Tips on Keeping Up on the Evidence

Earlier today, a resident commented that she just needed me to always be around to keep up on the evidence. While she was joking, it highlighted something that I have not been doing a good job of: showing you my tricks in staying up to date. I actually do not stay at home reading all of the journals. Even if I tried or wanted to, I would have three boys climbing all over me and a very unhappy wife! So how do I keep up to date? Are you ready for the curtain to be pulled back to reveal that it is all a scam? Well then, read on!
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Steroids for COPD: Oral Gets More Support

Many of us wouldn’t dream of not using steroids for a significant COPD exacerbation. We put it on the same level as not giving antibiotics for pneumonia or not giving aspirin for a patient having a heart attack. Despite this deeply engrained belief, the data behind steroid use for COPD exacerbations is shockingly small. I suspect most of you would be surprised to know that I was a second year medical student when steroids were really shown to be beneficial for COPD exacerbations (and no, I wasn’t a second year medical student in the 1980’s)1,2 . With this lack of data, there are many questions that have not been answered about steroid use for COPD exacerbations. Much of what we do, or actually ignore as you will see, is based upon consensus statements or small studies. The evidence for steroid use received a small boost in last months JAMA, although not as big of a boost as many of us would hope. In this blog I will review the evidence for steroid use, including the recent article. So read on as we look at a topic that should have overwhelming evidence, yet doesn’t!
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