Fact: I did not appreciate how important clinical trials would become in my every day life as an APPE student when I first took a biostatistics class during P1 year. Our ability to analyze and evaluate data from clinical trials is critical to providing evidence-based recommendations to our healthcare team. Although guidelines are also a great source of information, your preceptors will soon expect you know the landmark trials that set the foundation for the guidelines. When I first got out onto rotation I had no idea where to look for these landmark trials, so I asked, I googled, and I compiled. Now I have a pretty hefty dropbox filled with landmark trials relevant to each rotation I've been on! Since I'm currently on primary care, I figured I'd list some of the landmark trials we talk about the most and use the most in our every day practice.

Disclaimer: this is by no means totally comprehensive. I am very aware there are more trials than just these. These were picked at random and also listed at random. Also, I've tried not to enter in my own opinion because if I did I'd probably have a novel on my hands here.

1. SPRINT (2015)
Investigated if intensive BP control (target SBP <120 mmHg) in patients at high risk for CVD (without a history of stroke or diabetes) yielded CV outcomes superior to standard BP control (135-139 mmHg)

Primary end point: composite outcome of MI, ACS without MI, stroke, CV death and acute HF

Outcome: the trial was stopped after 3 years after an interim analysis showed superiority of intensive BP control compared to standard BP control. For the primary end point: 5.2% vs. 6.8%; P<0.001; NNT 63. There were more ADE (hypotension, syncope and AKI) observed in the intensive BP control arm.

2. ACCORD (2008) AND ACCORD-BP (2010)
Accord
Investigated whether intensive HbA1c goals (<6%) in patients with T2DM and baseline HbA1c >7.5% reduces the risk of CV events compared to standard HbA1c goals (7-7.9%)

Primary end point: annual rate of nonfatal MI or nonfatal stroke or CV death

Outcome: There was no difference in the primary end point between the two arms (2.11% vs. 2.29%; HR 0.90; 95% CI 0.78-1.04; P=0.16). The trial was stopped early (after 3.7 yrs) due to the observed increase in all cause mortality (NNH=370) and CV mortality. Now we only recommend intensive HbA1c lowering in certain populations.

Accord-BP
Does intensive BP control (SBP <120 mmHg) reduce the rates CV events when compared to the standard BP control (SBP <140 mmHg) in patients with T2DM and at high risk for CV events.

Primary end point: annual rate of nonfatal MI, nonfatal stroke or CV death

Outcome: There was no difference between the two study arms (1.87% vs. 2.09%; HR 0.88; 95% CI 0.73-1.06; P=0.20). JNC8 subsequently used this to determine their goal for diabetics (<140/90 mmHg). The intensive BP control arm did experience more side effects and were on more HTN medications compared to standard control (NNH 49).

3. IMPROVE-IT (2015)
Investigated whether the combination of ezetimibe and simvastatin reduces a composite CV outcome in patients with recent ACS compared to simvastatin monotherapy.

Primary end point: composite end point of CV mortality, nonfatal stroke or major CV event

Outcome: The combination of ezetimibe and simvastatin significantly reduced the rate of the composite primary end point (34.7% vs. 32.7%; P=0.016; NNT 50), but was most likely led by reductions seen in MI and stroke. The addition of ezetimibe to simvastatin provides about a 23-25% reduction in LDL-C. This trial hasn't changed practice very much, also worth noting the AAR was 2%.

4. UKPDS 34 (1998)
Investigated whether metformin reduces DM-related complications and all cause mortality when compared to other intensive agents and diet changes in newly diagnosed T2DM patients who are also overweight.

3 arms included metformin vs. diet vs. intensive treatment (chlorpropamide, glibenclamide or insulin)

Primary end point: all cause mortality, DM-specific mortality and DM-specific end points

Outcome: Metformin was associated with a reduction in all cause mortality DM related complications when compared to the other two arms but metformin vs. diet was the primary analysis. This trial is why we use metformin first line for newly diagnosed T2DM patients.

5. ACCOMPLISH (2008)
This trial compared the ability of benazepril/amlodipine vs. benazepril/HCTZ to reduce CV events in hypertensive patients at risk for CV complications.

Primary end point: composite of CV mortality, nonfatal MI, nonfatal CVA, UA, coronary revascularization or resuscitation after cardiac arrest

Outcome: Benazepril/amlodipine was associated with a reduction in the composite primary end point (9.6% vs. 11.8%; HR 0.80; 95% CI 0.72-0.90; P<0.001). Consider that they used HCTZ vs. Chlorthalidone for their diuretic (HCTZ is shorter acting and may be worse when it comes to 24 hour BP control).

6. SMART (2006)
Investigated whether use of a long-acting beta2 agonist (LABAs) in asthmatics increases mortality and other respiratory related ADE.

Primary end point: respiratory-related death or life-threatening events

Outcome: there was no difference found between the two arms for the primary composite end point. Importantly, there were increases observed in the following secondary outcomes: asthma-related deaths or life-threatening events, death from asthma and respiratory related death. These outcomes were more pronounced in subgroup analyses for African Americans and those not using corticosteroid inhalers. Because of this trial, LABAs are added to ICS in step 3 of asthma treatment, and they have a black box warning for asthma-related death.


7. EMPA-REG OUTCOME (2015)
Compared empagliflozin 10mg and 25mg to placebo in reducing composite end point CV event outcome in patients with T2DM at risk for CV events.

Primary end point: composite CV mortality, nonfatal MI or nonfatal stroke

Outcome: Reduction in the primary end point was observed with empagliflozin (10.5% vs. 12.1%; P=0.04). There was also an observed reduction in all-cause mortality and CV mortality. A1c reduction with empagliflozin was about 0.5%. Worth noting that the empagliflozin dose groups were pooled in the analysis.


8. LEADER (2016)
Investigated whether liraglutide reduced composite CV end point in T2DM patients at risk for CV events compared to placebo

Primary end point: composite of first occurrence of CV mortality, nonfatal stroke, or nonfatal MI

Outcomes: liraglutide achieved reduction in the primary end point (13.0% vs. 14.9%; HR 0.87; 95% CI 0.78 -0.97; P<0.001) and also showed statistical significance in the all-cause mortality analysis. Unfortunately, only modest reductions in HbA1c were observed and no one achieved an A1c <7%.

9. HOPE (2000) AND MICRO-HOPE
Hope
Investigated whether Ramipril reduces the rate of CV events with patients who have multiple CV risk factors but not heart failure.

Primary end point: composite of MI, stroke, and CV death

Outcomes: Ramipril signficantly lowered the rate of the composite primary end point (14.0% vs. 17.8%; HR 0.78; 95% CI 0.70-0.86; P<0.001; NNT 27). Benefits were seen in all sub group analyses, and there was a statistically significant reduction observed in all-cause mortality.

The MICRO-HOPE substudy investigated the effects of Ramipril on microvascular complications in T2DM such as microalbuminuria and nephropathy. Ramipril was found to also prevent overt nephropathy and have renoprotective effects.

10. HEART PROTECTION STUDY (2002)
Investigated whether simvastatin would reduce CV mortality and morbidity in those at high risk for CVD

Primary end point: All cause mortality, CV mortality, coronary mortality, vascular and non-vascular mortality

Outcomes: The reduction in all cause mortality caused by the simvastatin group was statistically significant (P=0.0003) vs. placebo, and there were benefits seen in coronary and vascular mortality. Essentially there was no LDL-C threshold where they didn't see a benefit, and effect did not differ based on baseline cholesterol.

11. CANVAS (2017)
Studied whether canagliflozin lowered the risk of CV events compared to placebo in patients with T2DM at high risk for developing CV events?

Primary end point: composite of CV mortality, nonfatal MI, nonfatal stroke

Outcomes: canagliflozin significantly reduced the rate of CV death and nonfatal CV events. There were also benefits seen in renal protection. Investigators saw a similar rate of reduction in HbA1c compared to empagliflozin (0.5%) but weirdly enough, canagliflozin was associated with an increased risk of amputation in this study.


12. TORCH (2007)
Investigated the ability of salmaterol/fluticasone combination therapy to reduce mortality in patients with COPD

Primary end point: All-cause mortality at 3 years and COPD-related mortality at 3 years

Outcomes: combination therapy slowed lung function decline, improved quality of life, and reduced exacerbations and hospitalizations. However the combo arm did not achieve statistical significance with the primary end point, despite there being a trend in reduction (P=0.052).

13. WISDOM (2014)
This study investigated whether you could safely taper inhaled corticosteroids off in severe COPD patients with stable symptoms who were on triple therapy (tiotropium, fluticasone and salmaterol).

Primary end point: time to first COPD exacerbation in the first 12mo after ICS withdrawal

Outcomes: ICS withdrawal does not increase the risk of COPD exacerbation and is generally safe. Basically this trial concluded that we have to weigh the risk with each patient. We don't know the long term benefits of withdrawing ICS but we do know they increase the risk for pneumonia, and they may also slow FEV1 decline. So assess on a patient-by-patient basis.

14. ALLHAT (2002)
This trial compared chlorthalidone, lisinopril and amlodpine in reducing CV events in patients with HTN

Primary end point: Fatal CAD or nonfatal MI at 6 years

Outcomes: Chlorthalidone emerged from underdog to super star. Compared to amlodipine it reduced the incidence of CHF, and compared to lisinopril it decreased the incidence of CAD, stroke, CHF and angina. Essentially this is where JNC8 got their first line agents. Alpha-antagonist doxazosin was dropped from this when they found it increased CHF compared to chlorthalidone.

15. JUPITER (2008)
Investigated whether rosuvastatin decreased the rate of CV events in patients with normal LDL-C and elevated CRP.

Primary end point: First major CV event (its a composite of a lot of CV outcomes)

Outcomes: Rosuvastatin reduced LDL-C, CRP and also the incidence of major CV events. However, the trial is widely criticized for being stopped early.

One of the cool things I get to do as an APPE pharmacy student at a primary care rotation is take blood pressures. I was never good at it in the past. I fumble with the cuff, always pick the wrong size, and usually make myself look like I just learned yesterday. Good news is, when you do something multiple times a day, every day, you start to get better. So it looks like I'm on my way to blood pressure pro status.

ANYWAY, today I decided to do a post about blood pressure. High blood pressure, or hypertension, is everywhere (in fact, one out of three Americans has high blood pressure!), and it complicates just about everything. I get a lot of questions from my non-medical friends about what blood pressure is, what it does, and how to prevent it. On the other side, the question for us in medicine usually is: what is the patient's goal, and which guideline!?


Pathophysiology
Overall, there are many mechanisms that go awry in patients with essential hypertension. It is first important to understand the different between your SYSTOLIC blood pressure (SBP) and your DIASTOLIC blood pressure (DBP). Both of these represent the pressure on the arterial wall when blood pumps through.

SBP: the pressure at the peak of heart contraction
DBP: the pressure after contraction when the chambers of the heart are filling with blood

During the whole cardiac cycle, we spend more time, 2/3 of the time, filling the heart (or in diastole) than in systole. SBP is usually determined by your cardiac output, or how much blood your heart is putting out into the body. DBP is usually determined by what is called systemic vascular resistance, a term used to define how difficult it is for your body to actually bump that blood out. Both CO and SVR are really important factors in the development of hypertension, because when things go wrong with them the body has a series of compensatory mechanisms it turns on to try to get CO and SVR back to normal.

When you have an increase in your CO, it makes sense that your blood pressure increases. More blood pumping out of your heart, more volume that has to fit through your arteries, and that leads to more pressure on the walls of those arteries! So what leads a person to have an increased CO?  One of the mechanisms is an increase in the blood in your heart's preload, or the amount of blood in the heart right before it contracts. More in = more out. This can happen due to an increase in your sodium intake, or problems with your kidney's ability to kick sodium out of the body. Where sodium goes, water follows, always! This one of the ways poor diet can result in high blood pressure. Poorer diets tend to be fully of salty foods, and eating all this salt attracts water, which affects your heart because suddenly theres a lot more blood than it is used to!

An increased CO can also happen when you have an increase in the constriction of your veins, the vessels bringing blood back to the heart. Remember I mentioned our bodies have compensatory mechanisms for when things get weird in the body? Well these are activated when our pressure is too low or too high. We have receptors and cells in our heart and kidneys that are meant to detect these changes, and get us back to our normal. After a while though, the increased stimulation of these pathways causes them to activate when they're not needed. The main two are the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (which controls the release of norepinephrine). Both of these systems release hormones, angiotensin II and norepinephrine, whose goal is to increase the blood pressure. Now in a situation where you are severely dehydrated and have low blood volume, this is great! This keeps you alive! But when these are being inappropriately released and cause constriction and ultimately an increased CO, this is bad.

The inappropriate action of these two systems also causes increased SVR as well. These hormones increase constriction, increased constriction means trying to fit a whole lot of blood through a way tinier vessel than your body is used to, which means it is also way harder for your body to get it through. Thats increased SVR! These hormones also cause an increase in structural hypertrophy from repeated activation. This means the cells get larger and grow more. The vessels become rigid, and narrow. Because of this, they are less likely to respond appropriately to changes in blood pressure.

Risk factors
So how exactly does this all start? How do external factors and your every day life play a role? And more importantly, who is at risk?

• Age >45yo men and >65yo women
• Having diabetes
• Increased cholesterol
• Race (black or hispanic individuals especially)
• Family history
• Being overweight or obese
• Using tobacco
• Physical inactivity
• Diet (too much sodium, too little potassium)
• Drinking too much alcohol
• Stress

Source: CDC

Symptoms
Usually people don't have any! High blood pressure is often known as a silent killer because you usually don't experience any symptoms until it is too late, meaning until you already have organ damage. See below.

Complications
So what is the big deal about high blood pressure, right? Why do we care? We care because of the long term complications. Your body can only keep up with a state of high blood pressure for so long before your organs start to suffer the consequences:


Preventing high blood pressure
There are certain risk factors you can change, and ones you can't. You can't change your age, or your genetics, but you can change your diet and your physical activity! Eating a well-balanced diet is key, and that means keeping how much sodium you consume <2.4g. Processed and prepackaged foods are notorious for being full of salt, and while its hard to cut salt out at all, its important to be vigilant about how much you're consuming. Limiting alcohol is something you also have control over. It's recommended that men drink <2 drinks per day, and women <1. The AHA recommends 150 min of moderate-intensity exercise a week, so whether its parking a little farther away from work or going on post-dinner walks, it is important to try to get that in. Shedding 10 lbs and keeping up with consistent exercise is known to work magic on blood pressure.

Different goals
Now this is probably where every non-medical student tunes out. There are many guidelines and therefore blood pressure goals for individuals out there. How do you know which to use!? It really is patient specific.

JNC8
-Summary algorithm
-The guidelines

I typically gravitate toward JNC8 when I have a patient without any other conditions. So I use it for my patients who don't have heart disease, kidney disease, or diabetes, but do have hypertension.

The guideline goal recommendations: If you're greater than 60yo your goal is <150/90, if you're literally anyone else its <140/90. Look at the summary algorithm above for a great picture analysis, I have this printed and kept in my white coat pocket because it is so fantastic.

American Heart Association
-The guidelines

For my patients with heart disease as their primary problem, I use the AHA guidance for blood pressure goals. This includes patients with heart failure, coronary artery disease, and acute coronary syndrome.

The guideline recommendations: If you have CAD, ACS or HF your goal is <140/90, if you have CAD and are post-heart attack, stroke, TIA, have carotid artery disease, PAD or abdominal aortic aneurysm, your goal is <130/80.

American Diabetes Association
-The guidelines

This is becoming kind of obvious right? I go here for my patients with diabetes.

The guideline recommendations: If you just have plain 'ol diabetes it's <140/90, but if you have diabetes, protein leaking from your kidneys or you also have ASCVD risk factors, go with <130/80

KDIGO
-The guidelines

If your patient has chronic kidney disease, you want to go to KDIGO. If they have pretty simple CKD your goal is <140/90, and if you have protein in your urine its going to be <130/80.


The bottom line

So what if you have a patient with hypertension, diabetes AND chronic kidney disease!? That is the patient I see just about everyday. This is where professional judgement comes in. Right now there is no ultimate guideline that says "LOOK HERE" for your complicated patient. It really just depends on their clinical picture and what you think they can tolerate (remember, pushing too low can be dangerous!). Luckily, a lot of the recommendations do overlap and it makes it easier for those with a lot of complications from their disease states. JNC8 included a nice table summary in their guidelines of all the other guideline recommendations. I highly advise printing it and keeping it with you if you can:



Thats about it for my review! I hope this was helpful. It is so important for patient and provider to fully understand high blood pressure and the consequences it can have if left uncontrolled. It is a modifiable risk factor in many diseases and if controlled can lead to a lot better outcomes for our patients.

A final disclaimer: this is not supposed to be completely comprehensive and is just supposed to serve as a simple review. Feel free to leave any comments or suggestions below!

It is impossible to not learn a lot from working in an emergency department. You learn a lot because you see a lot. You see codes, you see intubations, you see really sick elderly folks and really sick young adults. You see death, and you see recovery. You see countless antibiotics, psych meds, fluids, pain meds, heart meds, and just about every other class of medication you can think of. You see frustration, hope, pain, worry, resilience, and strength. In the ED you see it all. You see it all because the ED is a spectrum, where the team takes care of patients with problems as minor as a headache, to as severe as sepsis.

Now, emergency med is a rapidly evolving field when it comes to pharmacy involvement. There are more pharmacists than ever staffed in EDs and we do a lot to prevent drug errors, help with admission and discharge, and provide counseling. I've already done a previous post on all the great things ED pharmacists do, but I also wanted to include some cool resources for my fellow students to look at if you're interested in emergency med and want to learn more. This APPE taught me that self-directed learning is really important to keeping up with the crowd. Not only is the environment fast-paced, but you have to keep up with scores of new information daily as well. One day we're not recommending antibiotics with I&D for simple abscesses, the next there's a journal article shaking up the conversation! How do you keep up? You seek out information as much as possible, and lucky for us in the technology age, there are a lot of savvy ways to do it.

Here are some of my favorite resources:

1. Follow the #FOAMed hashtag on twitter!

FOAMed stands for "free open access medical education". It was created with the idea that of sharing information for students and professionals in a way that is accessible and available on different platforms. It has even resulted in the formation of conference: SMACC or Social Media and Critical Care. No matter the platform (social media, podcasts), you can find some sort of FOAMed and therefore tons of FREE resources!! There is even a specific student website! For more info on FOAMed check out this brief summary article.

2. Academic Life in Emergency Medicine or ALiEM

Another great website filled to the brim with resources for students and professionals. This website also has a series of modules you can read through and complete on different subjects relevant to emergency med professionals (such as SSTIs, fluids, etc.).

3. Connect with emergency med pharmacists on twitter

Using your professional twitter, of course. Following pharmacists on twitter has provided me with a TON of information relevant to the field. This was my most utilized way of seeking out new information, including journal articles!

Some of my favorites include my very own preceptor, @TheEDpharmacist, plus @EMpharmgirl, @PharmERtoxguy and @Nadia_EMPharmD

Not to mention, a lot of organizations have speciality specific twitters, like ASHP! And the previously mentioned website, ALiEM has a nice twitter as well!

4. Sign up for a journal feed!

My favorite one is literally called JournalFeed, and they're great because they send an article straight to your inbox and give you a quick 60 second summary so you get a quick and easy way to learn! This is the only one i've been able to find so far, but if you have a great one you've found feel free to comment below!

One of the things I LOVED about emergency med was the social media activity of the community. All healthcare professionals are using social media more and more to communicate information but it seems like right now, the emergency med professionals have super strong presence. Utilizing resources like these are critical when it comes to staying an up-to-date, active learner. I'm grateful for the pharmacy skills that this ED rotation taught me, but also for inspiring me to change how I look for my knowledge. I'm seriously going to miss this place, but I'm excited to share some of my primary care adventures with you all in the next few weeks!

Have an other emergency med resources that you love?! Comment below to share!

Hi everyone! It has been quite some time since I've done a brush letter pharm, so today I decided to do 3 of them! I've seen these agents sporadically in my emergency med rotation and thought they were pretty interesting drugs to cover. Each of them has interesting quirks so I hope you appreciate the science behind them!



Fosfomycin
Mechanism of action: inhibits bacterial cell wall synthesis by inactivating pyruvyl transferase, an important enzyme in the creation of bacterial cell walls

Spectrum of coverage: Gram positive agents (staph, strep) and gram negative (E.coli, H.influenzae, Neisseria spp., Salmonella and Shigella)

ADR: headache, dizziness, diarrhea, nausea

Fun facts!

• This drug remains concentrated in the urine for up to 48 hours which makes it a really useful one dose agent for women with UTIs
• The FDA approved indication is for women with uncomplicated cystitis, but I've seen it increasingly used in the ED for men (complicated UTI) due to case studies that support its use