Liberal Changes to rt-PA Contraindications for Acute Ischemic Stroke

Flying in under the radar recently were the changes to the Alteplase (rt-PA) prescribing information. These changes pertain to the contraindications to use of the drug in acute ischemic stroke. It’s hard to find anything on the particulars about why the FDA authorized such changes, and more puzzlingly, why.

The updated contraindications now read as follows: Link
Do not administer Activase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit:

  • Current intracranial hemorrhage 
  • Subarachnoid hemorrhage 
  • Active internal bleeding 
  • Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma 
  • Presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms) 
  • Bleeding diathesis 
  • Current severe uncontrolled hypertension

Without the old contraindications to compare to side by side, the changes may not be obvious. From a 2013 package insert, the contraindications read as follows (changes italicized)

Activase therapy in patients with acute ischemic stroke is contraindicated in the following situations because of an increased risk of bleeding, which could result in significant disability or death:

  • Evidence of intracranial hemorrhage on pretreatment evaluation
  • Suspicion of subarachnoid hemorrhage on pretreatment evaluation
  • Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or previous stroke
  • History of intracranial hemorrhage
  • Uncontrolled hypertension at time of treatment (e.g., > 185 mm Hg systolic or > 110 mm Hg diastolic)
  • Seizure at the onset of stroke
  • Active internal bleeding 
  • Intracranial neoplasm, arteriovenous malformation, or aneurysm
  • Known bleeding diathesis including but not limited to:
    • Current use of oral anticoagulants (e.g., warfarin sodium) or an International Normalized Ratio (INR) > 1.7 or a prothrombin time (PT) > 15 seconds
    • Administration of heparin within 48 hours preceding the onset of stroke and have an elevated activated partial thromboplastin time (aPTT) at presentation.
    • Platelet count < 100,000/mm3

The changes can be significant, particularly the language introducing the contraindications. The consequences use to be “significant disability or death” are now simply “situations in which the risk of bleeding is greater than the potential benefit.” If you didn’t catch the specific changes, rt-PA is no longer contraindicated in patients with:

  • History of intracranial hemorrhage
  • Seizure at the onset of stroke
Furthermore, the language describing specific bleeding diatheses (drugs: warfarin, diabigatran, rivaroxaban, etc.; thrombocytopenia or prolonged bleeding times) and describing what constitutes “uncontrolled hypertension” are now very vague. 
At this point the guidelines have not updated their list of contraindications… for now.

Advice to Future Residents From the Ghost of a Skeptical Student’s Past

When I began pharmacy school several years ago the thought of pursuing a residency wasn’t even on the radar. Like most other students at the time, I had a community pharmacy background and when the topic of post-graduate education was introduced I questioned its utility. I asked the important questions. Do I see myself working in a clinical setting? Is the extra year(s) of work and countless projects really worth it? Seriously you guys, who let the dogs out?

It’s clear that a paradigm shift is underway. Student interest in clinical pharmacy has never been higher, and subsequently, residency positions are now more difficult to achieve. Although the number of emergency medicine (EM) programs entering the Match has nearly tripled over the past five years (Table 1), the amount of post-graduate year two (PGY2) applicants has also risen by 78%.1

EM Programs
EM Positions
Total
Filled Early
Into Match
Total
Filled Early
Into Match
Filled via Match
2014
20
7
13
24
10
14
12
2013
15
4
11
18
5
13
11
2012
12
3
9
13
4
9
7
2011
10
3
7
11
3
8
6
2010
7
1
6
8
1
7
5

Table 1: National Matching Services statistics on emergency medicine PGY2 programs and positions.

As this year’s interview process comes to a close and the Match lingers right around the corner, ambitious new faces will soon fill the roles others have left behind. Given the increased competition for specialty residency positions, it is crucial to take advantage of the opportunities a PGY1 can offer if you’re throwing your hat in the ring for a PGY2. Here are five tips to help make the most of your PGY1 residency and improve the odds of landing that sought after EM PGY2 position.

5. You never get a second chance to make a first impression. Retrospectively identifying things we would have done differently the second time around is easy; the trick is anticipating these issues before they happen. Don’t forget the little things: dress sharp, smile, and maintain an appropriate amount of eye contact (experts recommend about 50% of the time while speaking and 70% of the time while listening). Advocate professionalism, but be yourself. Rehearse your presentations beforehand and anticipate questions that may be posed. Unfortunately we can’t hop into the DeLorean for a second chance, so do it right the first time. The fuel efficiency on that thing was probably terrible anyways.

4. Never underestimate the power of networking. I can’t tell you how many times I’ve heard the phrase “pharmacy is a small world” before. Not until one reaches their respective specialty does this statement become most true. Whether it’s grand rounds, a conference luncheon, or an afterhours speakeasy, meaningful conversation can go a long way.

3. Keep your friends close and your preceptors closer. Making friends outside of the hospital is beneficial for a work-life balance; however, building professional relationships with your preceptors on the inside is equally important. There’s a great chance these individuals may become the life-long mentors who help shape your career. Foster these relationships early and asking for positive letters of recommendation will be much easier when the time comes.

2. Tailor your experiences toward your goals. Trying to obtain a PGY2 in EM? Schedule EM and/or critical care rotations prior to Midyear so you can discuss your experiences. Ask to become involved with policy development or updating institutional guidelines related to the care of emergency medicine or critically ill patients. Volunteer an extra weekend shift or two with your preceptor.  Going above and beyond the minimum requirements will provide valuable learning experiences that will stand out on applications.

1. Emergency medicine is changing every day. Be the catalyst, not the anchor.Social media such as Twitter and related movements (e.g. FOAMed, FOAMRx, EMPOWER Podcast, etc.) have made it possible to receive the most recent evidence based literature at our fingertips, faster than ever before. Take advantage of these platforms to remain at the forefront of this constantly evolving profession. Don’t rely on information you were taught years ago, it may be outdated. Things are the way they are until they aren’t. So ask questions. Stay hungry to create change. Don’t be afraid to have a voice, and have the courage to challenge the dogma that every so often confines our clinical practice.

Finally, no one has ever said residency is easy. It will challenge you, force you to step outside of your comfort zone; you wouldn’t be able to grow if it didn’t. There will definitely be days when you wake up with too much work and not enough sleep, wondering if it’s all worth it. Trust me, I’ve asked myself the same question countless times. But as I prepare for the transition into the next chapter of my career, I reflect upon the knowledge gained, unique opportunities afforded, and professional relationships built. And now with only 4 months left of my EM residency, when asked if it’s really all worth it, I’ll give you the same answer every time…

Absolutely.

References:

1. National Matching Services, Inc. Accessed electronically via https://www.natmatch.com/ashprmp/aboutstats.html on March 1, 2015.


Kyle DeWitt, BS, Pharm.D. (@EmergPharm)
PGY2 Emergency Medicine Pharmacy Resident
University of New Mexico Hospital