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Episode 101: HOT TOPICS: Nicardipine versus Clevidipine

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Description

The efficacy of Nicardipine versus Clevidipine in treating neurocritical care patients is an ongoing debate which strongly divides opinion; and so in this week's episode, Dr Alex Reynolds is joined by Colleen Bond, PharmD, and Andy Webb, PharmD, who from a pharmacy standpoint help us to navigate the debate and further our understanding of the pros and cons of each agent.

Contributors

  • Andy Webb, PharmD

  • Colleen Bond, PharmD

  • Alexandra Reynolds, MD

    Alexandra Reynolds, MD, is an Assistant Professor of Neurosurgery and Neurology and a board-certified neurointensivist in the Neurocritical Care Unit at The Mount Sinai Hospital. Dr. Reynolds also serves as the Director of TeleNeurocritical Care for the Mount Sinai Health System.

    A native New Yorker, she was educated at Princeton University and the Columbia University College of Physicians & Surgeons before completing a neurology residency at NewYork-Presbyterian/Columbia University Medical Center and a Neurocritical Care fellowship at NewYork-Presbyterian/Columbia University Medical Center and Weill Cornell Medical Center.

    Dr. Reynolds is an expert in the treatment of neurological emergencies such as subarachnoid hemorrhage, intracerebral hemorrhage, status epilepticus, and neurotrauma. Her research centers on assessment, treatment and neurological prognostication of survivors of cardiac arrest and the neurological management of patients in fulminant hepatic failure.

  1. 00:00:22
    Alright, hi everyone. My name is Alex
  2. 00:00:24
    Reynolds. I am the host of the Hot
  3. 00:00:26
    Topics Neurocritical Care Society
  4. 00:00:29
    Podcast. I am a neuro intensivist at
  5. 00:00:33
    Mount Sinai Hospital. And I just want
  6. 00:00:36
    to remind you all before we start that
  7. 00:00:38
    you can access the Neurocritical Care
  8. 00:00:39
    Society Podcast anywhere you get your
  9. 00:00:41
    pods. Add us to your favorites and be
  10. 00:00:44
    sure to never miss an episode And also
  11. 00:00:47
    that NCS offers free continuing
  12. 00:00:49
    education credits for listening to
  13. 00:00:50
    select episodes. So if you listen via
  14. 00:00:53
    the NCS Learning Center and complete a
  15. 00:00:55
    short survey, you can receive your free
  16. 00:00:57
    credits. So I'm really excited to
  17. 00:01:00
    introduce two pharmacists today who are
  18. 00:01:04
    going to be participating in a pro-con
  19. 00:01:08
    debate about two of the controversial
  20. 00:01:11
    medications in the neuro-critical care
  21. 00:01:14
    community. So with us today, we have
  22. 00:01:18
    Colleen Bond. She is
  23. 00:01:22
    a PharmD, who works at Westchester
  24. 00:01:23
    Medical Center, and she rotates both in
  25. 00:01:26
    the emergency department and in the
  26. 00:01:28
    neurocritical care unit. And then we
  27. 00:01:31
    also have Andy Webb, also a PharmD from
  28. 00:01:35
    the Massachusetts General Hospital. And
  29. 00:01:39
    our hot topic today is going to be the
  30. 00:01:41
    use of my cardipine versus clavidipine
  31. 00:01:45
    in patients who have neurocritical care
  32. 00:01:47
    disease processes So first of all, I
  33. 00:01:50
    just want to introduce both of you and
  34. 00:01:52
    say hello and thank you so much for
  35. 00:01:53
    joining us. Yeah, thank you so much
  36. 00:01:56
    for having us. Simon, be here. So I
  37. 00:02:00
    think, you know, one of the
  38. 00:02:02
    controversies that we have seen in
  39. 00:02:06
    neurocritical care is the efficacy of my
  40. 00:02:09
    cardipine versus clavidipine. And I
  41. 00:02:12
    know that this can be one of those
  42. 00:02:15
    topics divides people strongly into
  43. 00:02:19
    either one camp or the other, and I'm
  44. 00:02:21
    wondering maybe Andy if you could sort
  45. 00:02:23
    of give us an overview from a pharmacy
  46. 00:02:26
    standpoint of why this has become a
  47. 00:02:28
    question at all, and why people have
  48. 00:02:31
    such dramatic responses to this question.
  49. 00:02:34
    Yeah, definitely. So I think we can
  50. 00:02:35
    all agree that in a lot of our patients
  51. 00:02:38
    really blood pressure plays a role in
  52. 00:02:41
    some capacity for a number of our kind
  53. 00:02:43
    of key diagnoses So be that a schematic
  54. 00:02:44
    stroke or interest rubral hemorrhage or
  55. 00:02:47
    subarachnoid hemorrhage or even
  56. 00:02:48
    traumatic brain injury. Oftentimes
  57. 00:02:50
    we'll set some systolic blood pressure
  58. 00:02:52
    goal, which what goal you set would be
  59. 00:02:54
    the topic for a whole separate podcast.
  60. 00:02:56
    But for the most part, we're going to
  61. 00:02:58
    be oftentimes bringing blood pressures
  62. 00:02:59
    down with some drug. And most of the
  63. 00:03:02
    time when patients who are admitted to
  64. 00:03:04
    the neuro ICU usually the easiest or the
  65. 00:03:07
    most kind of straightforward way to
  66. 00:03:09
    achieve that goal is doing some
  67. 00:03:11
    continuous infusion And, you know,
  68. 00:03:13
    sometimes it's maybe because patients
  69. 00:03:15
    already failed and intermittent. IV
  70. 00:03:17
    push of libetal or hydralisine or for
  71. 00:03:19
    whatever reason, they're so refractory
  72. 00:03:20
    to other agents that we go right to a
  73. 00:03:22
    continuous infusion. And for the most
  74. 00:03:24
    part in the neuro ICU, our two options
  75. 00:03:27
    are mostly gonna be nichardopine or
  76. 00:03:28
    clovidopine. You can make the
  77. 00:03:31
    argument for libetal all or some of the
  78. 00:03:32
    other beta blocker infusions, but
  79. 00:03:34
    really those two agents are gonna be the
  80. 00:03:35
    things that are the two agents available.
  81. 00:03:38
    And a lot of the controversy comes from
  82. 00:03:40
    basically debate over whether or not
  83. 00:03:42
    there are differences in how well they
  84. 00:03:44
    work, how fast they work, whether or
  85. 00:03:45
    not there's differences in the ability
  86. 00:03:47
    to achieve your goals. And the big
  87. 00:03:49
    thing that's oftentimes relevant is cost.
  88. 00:03:51
    And so the two of them are quite
  89. 00:03:53
    disparate in the cost and it also varies
  90. 00:03:56
    on how institutions compound each of
  91. 00:03:58
    them if they compound it at all. And so
  92. 00:04:01
    there's a lot of variability in
  93. 00:04:03
    basically access to any of the
  94. 00:04:04
    medications, how fast you can get it to
  95. 00:04:06
    the bedside, how fast you can titrate
  96. 00:04:08
    it and kind of how people are
  97. 00:04:10
    comfortable using one over the other. a
  98. 00:04:12
    lot to a large degree that's really how
  99. 00:04:14
    we've gotten into this controversy so to
  100. 00:04:16
    speak as to whether or not one is better
  101. 00:04:17
    than the other. Awesome. So maybe
  102. 00:04:22
    Colleen, can you comment a little bit
  103. 00:04:24
    about cost issues between Nicardipine
  104. 00:04:27
    and Clovidipine? Yeah, absolutely. So
  105. 00:04:31
    I think just for everyone to know,
  106. 00:04:36
    Clovidipine comes in a premixed vial
  107. 00:04:38
    that's ready to use and Nicardipine does
  108. 00:04:41
    come in premixed preparations, but also
  109. 00:04:45
    you can prepare these in your pharmacy
  110. 00:04:48
    as well. So I think depending on what
  111. 00:04:50
    institution you work at, you may have
  112. 00:04:53
    different things available to you. But
  113. 00:04:57
    because Clovidipine is one of the newer
  114. 00:05:00
    agents and kind of a third-generation
  115. 00:05:03
    agent, it does carry with it a cost.
  116. 00:05:07
    And it is, you know, can be, when we
  117. 00:05:11
    looked at it, year, we use a
  118. 00:05:12
    compounded product. It was twice as
  119. 00:05:15
    much to use clavitapine, but could be
  120. 00:05:18
    even more substantial, depending on
  121. 00:05:20
    what sort of contracts you're available
  122. 00:05:22
    to get through your pharmacy. So each
  123. 00:05:25
    institution that costs difference is
  124. 00:05:26
    going to be different, depending on
  125. 00:05:30
    what products you have and what
  126. 00:05:32
    contracts you have. But the cost will
  127. 00:05:35
    always be more for clavitapine versus
  128. 00:05:38
    nicardapine
  129. 00:05:40
    All right, and so Colleen, I think
  130. 00:05:42
    you're going to maybe - I gave you that
  131. 00:05:44
    question so that you could sort of be
  132. 00:05:46
    team nicardapine for today. And Andy's
  133. 00:05:49
    going to be team clavitapine, although
  134. 00:05:51
    just for everyone to know that Colleen
  135. 00:05:54
    and Andy are both taking sides for the
  136. 00:05:57
    sake of academic argument. And we'll
  137. 00:05:59
    ask them at the end what their real true
  138. 00:06:01
    feelings are before we let them go But
  139. 00:06:05
    so I wonder then, Colleen, like. Do
  140. 00:06:08
    you think cost is the major reason to
  141. 00:06:10
    avoid using clovidapine? Or do you
  142. 00:06:12
    think there are other reasons to prefer
  143. 00:06:15
    my cardopine? Yeah, I think that's a
  144. 00:06:18
    great question. I think the cost is
  145. 00:06:20
    definitely a factor. I think when you
  146. 00:06:23
    look at the pharmacokinetics of the two
  147. 00:06:26
    agents, it seems like clovidapine would
  148. 00:06:30
    be a real slam dunk and would really be
  149. 00:06:32
    the agent that would get you where you
  150. 00:06:35
    need to be And as Andy alluded to,
  151. 00:06:37
    we're trying to bring people's blood
  152. 00:06:39
    pressures down and those goals,
  153. 00:06:40
    obviously are going to be different for
  154. 00:06:41
    each patient. But when they have kind
  155. 00:06:45
    of studied this in the neurologic
  156. 00:06:46
    patients, whether it be hemorrhagic or
  157. 00:06:49
    ischemic strokes, trying to hash out
  158. 00:06:52
    who can get me to my goal systolic blood
  159. 00:06:55
    pressure, they haven't really been able
  160. 00:06:58
    to show that. And so I think that you
  161. 00:07:03
    have costs, but you also have clinical
  162. 00:07:05
    efficacy to think about as well.
  163. 00:07:10
    All right, and I think, yeah, that is
  164. 00:07:11
    a big question, usually is how fast can
  165. 00:07:14
    we start getting the blood pressure down?
  166. 00:07:17
    Andy, I wonder if you can comment or
  167. 00:07:19
    maybe even educate us more about this
  168. 00:07:22
    purported shorter half-life of
  169. 00:07:24
    elimination. 'Cause I think that's what
  170. 00:07:26
    a lot of people cite for the reason to
  171. 00:07:28
    use Clivitapine. Yeah, definitely.
  172. 00:07:30
    And that's really the main driver of its
  173. 00:07:32
    development, right? And so Clivitapine
  174. 00:07:33
    was intentionally designed to be this
  175. 00:07:34
    rapid acting, easily titratable, high
  176. 00:07:34
    response rate calcium channel blocker.
  177. 00:07:34
    And so Clivitapine, I think
  178. 00:07:41
    some people oftentimes forget just how
  179. 00:07:44
    long it's some of its onset and duration
  180. 00:07:46
    actually is. And so we think of
  181. 00:07:47
    Clivitapine as, you know, this nice,
  182. 00:07:47
    titratable, continuous infusion. But
  183. 00:07:47
    sometimes we conflate that with, say,
  184. 00:07:47
    our pressers, which are almost like
  185. 00:07:47
    instant on and off. But Clivitapine's
  186. 00:07:47
    onset of action is
  187. 00:07:50
    anywhere up
  188. 00:07:56
    to 30 minutes and its duration of
  189. 00:08:00
    activity at whatever rate that you set
  190. 00:08:03
    can be up to four hours and even longer
  191. 00:08:06
    in hepatic insufficiency patients are
  192. 00:08:07
    having challenge actually metabolizing
  193. 00:08:09
    the medication. And so my cardopene can
  194. 00:08:11
    take up to 15 to 30 minutes to actually
  195. 00:08:14
    start working. And then when you shut
  196. 00:08:15
    it off, say you've reached your goal or
  197. 00:08:17
    you've overshot your goal, it may stick
  198. 00:08:19
    around for quite a bit longer than that.
  199. 00:08:21
    It also has kind of bimodal elimination.
  200. 00:08:23
    So there's a somewhat faster half-life
  201. 00:08:26
    initially than a slower tail that kind
  202. 00:08:28
    of lingers for a long time. And that is
  203. 00:08:30
    highly variable dependent on patient's
  204. 00:08:32
    hepatic status. Where clavidopene was
  205. 00:08:34
    specifically designed to be basically
  206. 00:08:36
    metabolized by plasma esterases. So
  207. 00:08:37
    it's independent of hepatic function It
  208. 00:08:40
    essentially is there to almost instantly
  209. 00:08:42
    be metabolized within the serum itself.
  210. 00:08:44
    And because of that, it's onset of
  211. 00:08:46
    action is much faster. So it is an
  212. 00:08:48
    onset of action of about two to four
  213. 00:08:50
    minutes and a duration of action of
  214. 00:08:52
    anywhere from five to 15 minutes. And
  215. 00:08:55
    so the main advantage is that when you
  216. 00:08:57
    start clavidopene, you should be able
  217. 00:08:59
    to rapidly up-titrate it. So
  218. 00:09:01
    traditional titration instructions for
  219. 00:09:03
    nichardopene or you can go up by 25 to 5
  220. 00:09:06
    milligrams every five 15 minutes.
  221. 00:09:11
    where clavitapine is designed in such a
  222. 00:09:12
    way where you're supposed to be able to
  223. 00:09:14
    double the dose every 60 to 90 seconds.
  224. 00:09:17
    And so if clavitapine is kind of used in
  225. 00:09:19
    such a way to harness the capabilities
  226. 00:09:21
    of its pharmacokinetics, you should be
  227. 00:09:23
    able to really crank the dose up to
  228. 00:09:26
    achieve your goal in a very rapid
  229. 00:09:27
    fashion. And that's really the
  230. 00:09:29
    pharmacokinetic advantage that
  231. 00:09:30
    clavitapine has over my cardopine.
  232. 00:09:34
    So that was pretty, that sounds like
  233. 00:09:37
    what a pharma rep might tell me as a
  234. 00:09:40
    reason to use clavitapine. And I guess,
  235. 00:09:43
    Colleen, as a team like cardopine,
  236. 00:09:46
    what would you comment on, like, do
  237. 00:09:48
    you think that that sort of
  238. 00:09:50
    pharmacokinetics and pharmacodynamics
  239. 00:09:52
    are clinically relevant in our patient
  240. 00:09:55
    populations?
  241. 00:09:59
    So, I think that the pharmacokinetics
  242. 00:10:04
    are definitely different, right? And I
  243. 00:10:05
    think the data is there to show that,
  244. 00:10:07
    and I think the rapidity of which you
  245. 00:10:10
    can titrate up your clovidapine to
  246. 00:10:13
    feel like you're doing something, right?
  247. 00:10:16
    But oftentimes when you go into actual
  248. 00:10:18
    clinical practice, are you really
  249. 00:10:20
    taking a vital sign every 90 seconds to
  250. 00:10:23
    titrate up? Are you going to have
  251. 00:10:26
    an A line in the emergency department to
  252. 00:10:29
    be titrating every 90 seconds or really
  253. 00:10:32
    in clinical practice, do you have Q15
  254. 00:10:36
    vital signs and it's not really being
  255. 00:10:38
    titrated? So, I think it does have
  256. 00:10:42
    those pharmacokinetic profiles, but are
  257. 00:10:46
    we really set up to capitalize on them
  258. 00:10:49
    in clinical practice? I think is
  259. 00:10:52
    something to consider
  260. 00:10:56
    I guess another natural question then
  261. 00:11:01
    might be whether there is a disease
  262. 00:11:05
    specific reason to prefer one over the
  263. 00:11:07
    other, whether it be intracranial
  264. 00:11:10
    hemorrhage or the post-operative patient
  265. 00:11:12
    who might be at risk for intracranial
  266. 00:11:14
    hemorrhage or hypertensive emergency and
  267. 00:11:17
    press. Do you guys have any thoughts or
  268. 00:11:19
    do you know of any literature that kind
  269. 00:11:22
    of focuses on a specific disease process?
  270. 00:11:25
    Yeah, so I can start here. So I think,
  271. 00:11:27
    yeah, I think it's a great point that
  272. 00:11:29
    one of the main limitations of
  273. 00:11:30
    clavitapine is to take advantage of its
  274. 00:11:32
    kinetic differences, is you have to use
  275. 00:11:34
    it in such a way that you're taking
  276. 00:11:35
    advantage of the kinetic differences.
  277. 00:11:37
    And so I think that there is some data
  278. 00:11:38
    that suggests that if you do have the
  279. 00:11:40
    capacity to do that, you really can see
  280. 00:11:43
    some of the benefits. So the accelerate
  281. 00:11:45
    trial was one of the first prospective
  282. 00:11:48
    trials, at least specifically in the
  283. 00:11:49
    neurocritical care population, to kind
  284. 00:11:50
    of look at this. And so Accelerate was
  285. 00:11:52
    a relatively small single arm
  286. 00:11:55
    prospective study that enrolled patients
  287. 00:11:57
    with symptomatic, spontaneous
  288. 00:11:59
    intracranial hemorrhage who presented
  289. 00:12:01
    within the first six to 12 hours of
  290. 00:12:03
    onset and that elevated baseline
  291. 00:12:05
    systolic blood pressure above 160. And
  292. 00:12:07
    essentially the way that the study was
  293. 00:12:09
    designed was, and this kind of gets to
  294. 00:12:11
    some of the feasibility of doing this in
  295. 00:12:13
    clinical practice, is basically the
  296. 00:12:15
    investigator hung around and made sure
  297. 00:12:19
    that the clavitapine was used in a such
  298. 00:12:21
    a way to optimize its ability to control
  299. 00:12:24
    blood pressure. And so it was a tiny
  300. 00:12:26
    study, so they only enrolled 35
  301. 00:12:27
    patients and ended up excluding two
  302. 00:12:29
    because they were found to be ineligible
  303. 00:12:31
    afterwards. But in the 33 patients that
  304. 00:12:33
    they were able to analyze, when
  305. 00:12:35
    clavitapine was started and patients who
  306. 00:12:37
    had a baseline blood pressure like 180
  307. 00:12:39
    to 190, they reached their defined
  308. 00:12:42
    systolic blood pressure goal of less
  309. 00:12:43
    than 160 in about five minutes And so,
  310. 00:12:46
    if you do have the capacity to. control
  311. 00:12:50
    the dosing in such a way to optimize its
  312. 00:12:51
    kinetics, at least with some of the
  313. 00:12:53
    prospective data that we have, you
  314. 00:12:55
    really can achieve those goals in an
  315. 00:12:58
    extremely rapid fashion when you are
  316. 00:13:00
    kind of titrating the drug in such a way
  317. 00:13:02
    to kind of optimize that.
  318. 00:13:05
    I'm sure that that small study probably
  319. 00:13:07
    was not powered to see any difference in
  320. 00:13:10
    outcomes, but I'm wondering, do you
  321. 00:13:12
    think that either of you think that
  322. 00:13:14
    there's enough evidence to suggest that
  323. 00:13:16
    that rapidity of blood pressure control,
  324. 00:13:20
    I think, which I guess is we're talking
  325. 00:13:22
    about minutes to maybe an hour, do you
  326. 00:13:25
    think that that has functional sort of
  327. 00:13:28
    effects on outcome?
  328. 00:13:32
    Yeah, I guess it kind of depends. To a
  329. 00:13:34
    certain extent, I think that as you
  330. 00:13:36
    interpret some of the interact to and
  331. 00:13:38
    now interact three data, we at least
  332. 00:13:41
    show that achieving your goal, the
  333. 00:13:43
    faster you achieve your systolic blood
  334. 00:13:44
    pressure goal, the higher the
  335. 00:13:46
    likelihood you will have a I didn't get
  336. 00:13:49
    that the granularity of that speed has
  337. 00:13:52
    not quite been defined in the same way
  338. 00:13:54
    that say we have for TPA or connect a
  339. 00:13:56
    place where each minute will prevent
  340. 00:13:59
    disability into a certain degree. But
  341. 00:14:02
    you definitely could make the argument
  342. 00:14:03
    that some of the data with nichardopine
  343. 00:14:05
    where especially if you need to have
  344. 00:14:09
    nichardopine compounded in central
  345. 00:14:10
    pharmacy, like there was one study that
  346. 00:14:12
    was published out of a center that
  347. 00:14:14
    compounded their nichardopine centrally
  348. 00:14:16
    that had clivetopine available in the
  349. 00:14:17
    Omni cells or their dispensing cabinets
  350. 00:14:19
    in the emergency department where the
  351. 00:14:22
    time to blood pressure control was
  352. 00:14:24
    almost an hour faster in the clivetopine
  353. 00:14:26
    arm, mostly because it took so long to
  354. 00:14:28
    actually get the drug to the bedside.
  355. 00:14:30
    And so I think when you have some of
  356. 00:14:31
    those differences where the difference
  357. 00:14:33
    between getting the drug in the patient
  358. 00:14:35
    can be quite prolonged, you might
  359. 00:14:38
    actually start to see differences in
  360. 00:14:39
    outcomes, but at least I don't know if
  361. 00:14:41
    any data that's quite powered enough
  362. 00:14:43
    'cause we barely achieved that with our
  363. 00:14:44
    large prospective randomized control
  364. 00:14:46
    trials. that's successfully actually
  365. 00:14:48
    been able to see a difference between
  366. 00:14:49
    the two agents from a functional outcome
  367. 00:14:50
    perspective. Pauline, can you tell us
  368. 00:14:53
    more about compounding Nypertapine
  369. 00:14:56
    versus I know that they do have premixed
  370. 00:14:58
    bags and what's the advantage over
  371. 00:15:00
    compounding? Yeah, that's a great
  372. 00:15:03
    question. And I think
  373. 00:15:06
    each institution probably handles it a
  374. 00:15:08
    little bit different. So as I mentioned
  375. 00:15:10
    before, there are premixed bags
  376. 00:15:13
    available that come 20 milligrams or 40
  377. 00:15:16
    milligrams in a bag. And knowing the
  378. 00:15:19
    dosing that's available, often patients
  379. 00:15:21
    can require up to 15 milligrams per hour.
  380. 00:15:25
    So while it's ready to use,
  381. 00:15:29
    nurses would have to be going back to
  382. 00:15:31
    rehang new bags for these patients quite
  383. 00:15:34
    often. And also this comes with a great
  384. 00:15:37
    deal of volume that these patients would
  385. 00:15:39
    receive. The American Society of Health
  386. 00:15:42
    System Pharmacists actually publishes a
  387. 00:15:45
    paper looking at. standardized
  388. 00:15:47
    concentrations of medications for safety
  389. 00:15:50
    reasons. So in this document, they
  390. 00:15:53
    list nichardepine. You can make it in a
  391. 00:15:56
    01 milligram per ml or a 05 milligram
  392. 00:15:59
    per ml concentration. This more
  393. 00:16:02
    concentrated form of nichardepine is the
  394. 00:16:05
    same concentration
  395. 00:16:08
    that the premix qubitipine is available
  396. 00:16:09
    in.
  397. 00:16:11
    Now, while you can - you'd have to then
  398. 00:16:13
    have this product made within your
  399. 00:16:15
    pharmacy So you have to have the staff
  400. 00:16:19
    to be able to batch this and kind of
  401. 00:16:21
    know how much do you need to have on
  402. 00:16:23
    hand. Where are you going to store it?
  403. 00:16:26
    Do you have refrigerators in different
  404. 00:16:27
    areas that are able to keep this on hand?
  405. 00:16:31
    So
  406. 00:16:33
    there's a great difference in the
  407. 00:16:36
    availability based on your institution
  408. 00:16:39
    and what they've decided. Not every
  409. 00:16:41
    institution follows the American Society
  410. 00:16:44
    Health pharmacist standard concentration
  411. 00:16:46
    recommendations. They're just that a
  412. 00:16:48
    recommendation. So if you're a smaller
  413. 00:16:51
    institution and you're not having a high
  414. 00:16:53
    volume of patients requiring
  415. 00:16:56
    nichardepine, you may just be wasting
  416. 00:16:59
    resources pre-making these bags,
  417. 00:17:02
    expecting these patients to come in.
  418. 00:17:05
    Whereas if you're a higher volume center,
  419. 00:17:08
    may make more sense for your pharmacy
  420. 00:17:09
    department to compound these products,
  421. 00:17:12
    knowing that your usage will be there.
  422. 00:17:16
    That's really interesting, and going
  423. 00:17:18
    back to the fact that you work both in
  424. 00:17:20
    the emergency department and ICU neuro
  425. 00:17:22
    the in at Westchester, I wonder, do
  426. 00:17:25
    you think that there are reasons to
  427. 00:17:27
    compound in one place versus the other?
  428. 00:17:31
    Or I mean, I guess you're a pretty high
  429. 00:17:35
    volume center altogether, but I wonder
  430. 00:17:38
    if there are sort of reasons why you
  431. 00:17:40
    might decide to compound in one place
  432. 00:17:42
    rather than the other? Sure, I think
  433. 00:17:44
    that's a great question. And we've
  434. 00:17:46
    actually looked at this because this was
  435. 00:17:49
    a hot topic, evaluating whether or not
  436. 00:17:52
    to have COVID-19 available for patients
  437. 00:17:55
    at our institution. So this was one of
  438. 00:17:57
    the things we did look at. The volume
  439. 00:17:59
    of usage of our bags was pretty
  440. 00:18:03
    consistent between the emergency
  441. 00:18:05
    department and the neuroscience ICU.
  442. 00:18:08
    Most of those patients were initiated in
  443. 00:18:11
    the emergency department and then
  444. 00:18:13
    continued on these agents in the
  445. 00:18:15
    neuroscience ICU.
  446. 00:18:18
    So it's one pharmacy that services both
  447. 00:18:21
    of these areas. So if you're
  448. 00:18:23
    compounding it for one area, you'd be
  449. 00:18:25
    sending it to both. But one of the
  450. 00:18:28
    things to evaluate would be your PAR
  451. 00:18:30
    levels or how many should you have
  452. 00:18:32
    available in each of these areas at a
  453. 00:18:34
    certain time.
  454. 00:18:36
    Because if you are telling providers
  455. 00:18:38
    you're going to have something available
  456. 00:18:40
    to them for each ischemic stroke each.
  457. 00:18:44
    hemorrhagic stroke that comes in, you
  458. 00:18:46
    wanna make sure that it's actually in
  459. 00:18:47
    the refrigerator and it's not a stock
  460. 00:18:49
    out and you're causing a delay in that
  461. 00:18:52
    patient. So you wanna be able to have
  462. 00:18:54
    consistency in care. So your nursing
  463. 00:18:57
    staff and your providers have some
  464. 00:19:01
    consistency in what's available to them
  465. 00:19:02
    to practice.
  466. 00:19:05
    Got it. Andy, I wanna maybe switch
  467. 00:19:09
    gears a little bit and talk a little bit
  468. 00:19:11
    about how the two drips come. So
  469. 00:19:15
    Clovidapine is a lipid emulsion and I
  470. 00:19:17
    know a lot of our patients are also
  471. 00:19:18
    gonna be on propofol potentially. Do
  472. 00:19:21
    you think there's any sort of downside
  473. 00:19:25
    to having Clovidapine as a lipid
  474. 00:19:27
    emulsion? Yeah, so I think to a
  475. 00:19:29
    certain extent it's largely the same
  476. 00:19:31
    downside that we think about with
  477. 00:19:32
    propofol. Something that's a little bit
  478. 00:19:33
    different about Clovidapine is actually,
  479. 00:19:35
    is twice as much lipid per volume as
  480. 00:19:37
    propofol provide So that is one thing to
  481. 00:19:40
    recognize. is that when you're actually
  482. 00:19:42
    looking at clovidapine's packages or
  483. 00:19:44
    dosing, the reason that the packages
  484. 00:19:45
    are caps at 21 milligrams an hour is
  485. 00:19:48
    actually because that's the maximum
  486. 00:19:49
    recommended amount of lipid you should
  487. 00:19:52
    give a patient in a day. And so that is
  488. 00:19:54
    kind of one consideration is that
  489. 00:19:56
    hypertroglyceridemia and potentially
  490. 00:19:59
    pancreatitis associated with that. It's
  491. 00:20:01
    not something we typically think about
  492. 00:20:02
    with blood pressure meds, but when you
  493. 00:20:04
    do have a patient who is say on
  494. 00:20:07
    concomitant clovidapine and propofol, a
  495. 00:20:10
    serial monitoring of triglycerides is
  496. 00:20:12
    really important in this patient
  497. 00:20:13
    population. I think the good news is
  498. 00:20:15
    that even in some of the studies that
  499. 00:20:17
    have gone up to 32 milligrams an hour,
  500. 00:20:19
    which is like on the higher end, if not
  501. 00:20:21
    the highest dosing that's kind of
  502. 00:20:22
    reported in the literature, rates of
  503. 00:20:25
    significant hypertroglyceridemia are
  504. 00:20:27
    actually like quite low and even lower
  505. 00:20:30
    than you might expect with propofol
  506. 00:20:32
    where a lot of the relatively small
  507. 00:20:34
    retrospective studies and the very small
  508. 00:20:36
    prospective studies, many of them don't
  509. 00:20:38
    have any cases hyper-trogless for eating
  510. 00:20:40
    it at all. So at least in my own
  511. 00:20:42
    clinical practice, I have really yet to
  512. 00:20:43
    see some of those extreme
  513. 00:20:46
    hypertroglyceridemia cases that you
  514. 00:20:47
    sometimes see with propofol, which
  515. 00:20:49
    might get to differences in hepatic
  516. 00:20:51
    function of the processing of the
  517. 00:20:53
    different lipid products. But
  518. 00:20:55
    regardless, that is definitely
  519. 00:20:56
    something to keep in mind, that when
  520. 00:20:59
    you do have somebody running on
  521. 00:21:00
    clovidopine, not only do you need to
  522. 00:21:02
    monitor triglycerides, it's also
  523. 00:21:03
    providing calories. So you want to make
  524. 00:21:05
    sure that your dietitian is keeping
  525. 00:21:06
    track of the volumes of clovidopine
  526. 00:21:08
    patients or taking to account for their
  527. 00:21:10
    tube feed requirements if they're on
  528. 00:21:11
    tube feeds. And it's just like a
  529. 00:21:13
    slightly different way of monitoring
  530. 00:21:15
    than we typically think about with
  531. 00:21:17
    nichardopine. But other than
  532. 00:21:19
    that, kind of the advantage of having
  533. 00:21:21
    it in a lipid emulsion allows
  534. 00:21:22
    clovidopine to be more lipophilic and
  535. 00:21:25
    faster acting at the vascular level. So
  536. 00:21:27
    that is kind of the trade-off. We get
  537. 00:21:29
    these great kinetics, but we have to
  538. 00:21:31
    just deal with the fact that it's mixed
  539. 00:21:33
    in a lipid. But we're all very
  540. 00:21:34
    comfortable with monitoring propofol and
  541. 00:21:36
    some of the consequences that come with
  542. 00:21:37
    a little bit of mulch in there. So it
  543. 00:21:39
    shouldn't really be too much different
  544. 00:21:40
    than that. Right, interesting. And
  545. 00:21:43
    Nicotopean is in normal saline. Is
  546. 00:21:45
    there any data on rates of hypercleramic
  547. 00:21:47
    acidosis in patients or are the volumes
  548. 00:21:50
    really not that high?
  549. 00:21:57
    I'll say that I'm not familiar with that
  550. 00:21:58
    particular endpoint, but what I will
  551. 00:22:00
    say is there is good data that night
  552. 00:22:02
    card gives you a lot more volume. And
  553. 00:22:04
    so I think you could probably
  554. 00:22:06
    extrapolate that, you know, with the
  555. 00:22:08
    amounts of volume, it may contribute to
  556. 00:22:10
    hyperchleremia, but pretty consistently
  557. 00:22:12
    and almost every study you look at over
  558. 00:22:15
    the course of therapy or even in just
  559. 00:22:15
    the first 24 hours Patients get
  560. 00:22:19
    significantly more volume when they're
  561. 00:22:21
    on nichardopene versus clivettapene,
  562. 00:22:23
    which isn't necessarily the end of the
  563. 00:22:25
    world and a lot of our patients, but
  564. 00:22:27
    can be, especially if you have patients
  565. 00:22:28
    with cardiac pathology, that you do
  566. 00:22:30
    want to be very intentional about how
  567. 00:22:31
    much volume you're giving them I would
  568. 00:22:34
    like to comment too, it would depend on
  569. 00:22:36
    which prepared product that you were
  570. 00:22:38
    using, but the more concentrated
  571. 00:22:40
    preparation, if someone was on
  572. 00:22:43
    clivettapene 5 milligrams an hour, it
  573. 00:22:45
    would be about 10 ml per hour.
  574. 00:22:47
    Comparable doses of nichardopene of 10
  575. 00:22:50
    milligrams per hour in that concentrated
  576. 00:22:52
    form would only be 20 ml per hour. I
  577. 00:22:55
    think a lot of the trials that they did
  578. 00:22:57
    look at were using the ready-prepared
  579. 00:23:00
    Nicard opinion, which is probably what
  580. 00:23:02
    most institutions will have available to
  581. 00:23:05
    them.
  582. 00:23:09
    Um, I wonder about whether you think
  583. 00:23:12
    that there is a location in the hospital
  584. 00:23:16
    that lends itself more, whether it be
  585. 00:23:19
    the PACU or the emergency room or even,
  586. 00:23:22
    you know, on stroke ambulances, for
  587. 00:23:25
    example, where we may know even before
  588. 00:23:28
    the patients in the hospital that the
  589. 00:23:31
    patient has an ICH and needs blood
  590. 00:23:33
    pressure lowering. Do you have any
  591. 00:23:34
    thoughts about safety of using this in
  592. 00:23:38
    kind of non traditional areas, or do,
  593. 00:23:42
    you know, providers who are using these
  594. 00:23:44
    medications in the PACU or in an
  595. 00:23:46
    ambulance do they need to know anything
  596. 00:23:48
    in particular?
  597. 00:23:53
    I kind of just came up with that
  598. 00:23:54
    question, by the way. We'll cut that
  599. 00:23:56
    part out, but.
  600. 00:24:00
    And you can say it's a terrible question
  601. 00:24:02
    and we'll just cut the whole thing out,
  602. 00:24:03
    that's fine too. I think it's a unique
  603. 00:24:06
    question. I think because
  604. 00:24:09
    cost is a factor and I think that there
  605. 00:24:13
    is probably a place for a little bit of
  606. 00:24:17
    pain. I think people are trying to find
  607. 00:24:18
    that place while still keeping control
  608. 00:24:22
    of it So it's not initiated and
  609. 00:24:24
    continued for days and days and weeks.
  610. 00:24:29
    I think it really comes down to the,
  611. 00:24:33
    it's got a great pharmacokinetic profile,
  612. 00:24:35
    but I think
  613. 00:24:38
    it's really the
  614. 00:24:41
    putting it into practice and being able
  615. 00:24:43
    to titrate it that quickly. And a lot
  616. 00:24:46
    of times in these patients when they
  617. 00:24:47
    come into the emergency department,
  618. 00:24:49
    There's a lot going on. you know,
  619. 00:24:51
    they're getting their scans right away.
  620. 00:24:53
    You're maybe consulting neurosurgery.
  621. 00:24:56
    You're getting the neurology team on
  622. 00:24:58
    board. You're trying to get lines in
  623. 00:25:00
    these patients. You might only have one
  624. 00:25:02
    line. What other medications do they
  625. 00:25:04
    need? Clovid opinion has concerns with
  626. 00:25:09
    its ability to be run with other
  627. 00:25:10
    medications. So how many lines do you
  628. 00:25:12
    have at the moment? Do you need to stop
  629. 00:25:14
    it to give something else? You know, I
  630. 00:25:17
    think
  631. 00:25:19
    looking at the pharmacokinetics, the ED
  632. 00:25:21
    would make the most sense.
  633. 00:25:25
    You know, get that blood pressure down
  634. 00:25:27
    quickly and maybe this patient's a fast
  635. 00:25:29
    leader, right? They've been talking
  636. 00:25:30
    about that. It was like a fast leader.
  637. 00:25:35
    But there's a lot going on. So why my
  638. 00:25:37
    concern would be how do you do that in
  639. 00:25:43
    practice? How do you take the most
  640. 00:25:45
    advantage of this pharmacokinetic
  641. 00:25:46
    profile for the best benefit for the
  642. 00:25:49
    patient?
  643. 00:25:52
    Yeah, I would agree with that. The
  644. 00:25:54
    operational aspect can be challenging.
  645. 00:25:56
    I think one, obviously the advantage
  646. 00:25:58
    that might be particularly present,
  647. 00:25:59
    especially if you have like a mobile
  648. 00:26:01
    stroke unit, is the pre-mixed nature,
  649. 00:26:04
    if depending on that kind of stock of
  650. 00:26:05
    your hospital, click it if you usually
  651. 00:26:07
    get to be a little bit more readily
  652. 00:26:07
    available. Additionally, well, this
  653. 00:26:09
    like isn't the biggest concern most of
  654. 00:26:12
    the time. Nicartopene can be a
  655. 00:26:18
    peripheral IV irritant. And so if you
  656. 00:26:20
    do have kind of like a ratty peripheral
  657. 00:26:21
    IV, Nicartopene actually might not
  658. 00:26:21
    actually be the best agent if in case it
  659. 00:26:23
    kind of increases the risk of blowing
  660. 00:26:25
    that IV, where clovidopene tends to be
  661. 00:26:27
    a little bit better tolerated at the
  662. 00:26:28
    peripheral sites. Usually not too big
  663. 00:26:31
    of a concern. It's not the kind of
  664. 00:26:32
    thing where Nicartopene has to be given
  665. 00:26:34
    centrally. But it is one consideration,
  666. 00:26:36
    particularly if you're going to be
  667. 00:26:37
    giving this in the pre-hospital setting.
  668. 00:26:41
    I do want to ask about something that is
  669. 00:26:43
    somewhat anecdotal, I would say, but I
  670. 00:26:45
    have heard it from other colleagues as
  671. 00:26:46
    well, that there seem to be patients
  672. 00:26:48
    that just don't seem to respond well to
  673. 00:26:50
    nichardopene. And then you, you know,
  674. 00:26:52
    you're, you're maxed on my cardopene
  675. 00:26:54
    and they're really not doing much. And
  676. 00:26:55
    then you switch them to clovidopene and
  677. 00:26:57
    all of a sudden their, their blood
  678. 00:26:58
    pressure is responding. And I don't
  679. 00:27:00
    know if that's because of the
  680. 00:27:03
    pharmacokinetics of it or if there are
  681. 00:27:06
    other reasons that some patients might
  682. 00:27:08
    not be my cardopene responders.
  683. 00:27:12
    Yeah. So I, I personally have also had
  684. 00:27:14
    this experience where you have somebody
  685. 00:27:15
    who's on 15 of my card and their blood
  686. 00:27:17
    pressure is still hanging in the 170s
  687. 00:27:19
    And I've also had success getting their
  688. 00:27:22
    blood pressure under control with
  689. 00:27:23
    clavitopene. I think it's kind of tough
  690. 00:27:25
    to pinpoint why that might be the case.
  691. 00:27:28
    Like one thing that really is lacking
  692. 00:27:30
    across the board and all the literature
  693. 00:27:32
    is exactly what's a comparable dose
  694. 00:27:34
    between the two of them. There's no
  695. 00:27:36
    good conversion from nicardopene to
  696. 00:27:39
    clavitopene. So it very well might be
  697. 00:27:40
    that we just are comfortable going
  698. 00:27:42
    higher on clavitopene than the relative
  699. 00:27:44
    nicardopene dose would be, right? So
  700. 00:27:46
    like the literature supports going up to
  701. 00:27:48
    32 milligrams hour of Clivitapine and.
  702. 00:27:51
    who knows, maybe that's twice as much
  703. 00:27:53
    nichardepine. There's just not like
  704. 00:27:54
    studies looking at differences in
  705. 00:27:56
    vascular reactivity or from a dose based
  706. 00:27:59
    perspective. There is a little bit of
  707. 00:28:01
    evidence on this though. So there is
  708. 00:28:02
    one single center retrospective study
  709. 00:28:06
    out of Ohio State that specifically
  710. 00:28:08
    looked at post-operative neurosurgical
  711. 00:28:10
    hypertension in patients who had
  712. 00:28:12
    actually failed nichardepine. So they
  713. 00:28:14
    were not achieving their goal despite
  714. 00:28:16
    maxing out on nichardepine And in their
  715. 00:28:19
    whopping sample size of 12 patients,
  716. 00:28:22
    about a little over 90 of those patients
  717. 00:28:24
    did achieve their goal on clevatepine.
  718. 00:28:26
    And so it's while maybe 12 patients you
  719. 00:28:28
    could also call anecdotal, there's at
  720. 00:28:30
    least some support in the literature
  721. 00:28:31
    that if you are failing nichardepine
  722. 00:28:34
    before you start like cranking
  723. 00:28:36
    hydrolysine or some sub-optimal IV oral
  724. 00:28:40
    agent, there might be some credence to
  725. 00:28:43
    clevatepine having and a little bit of
  726. 00:28:44
    an edge in those calcium channel blocker
  727. 00:28:46
    resistant patients.
  728. 00:28:50
    Is there any sort of, I don't know the
  729. 00:28:52
    literature as well as you guys do, but
  730. 00:28:54
    what kind of data do you think we still
  731. 00:28:56
    need in order to settle these sorts of
  732. 00:28:58
    questions? Like, are there, if you
  733. 00:29:00
    guys could just create a couple of, you
  734. 00:29:03
    know, randomized trials and I gave you
  735. 00:29:04
    all the money, like, what would be
  736. 00:29:06
    your dream questions to answer
  737. 00:29:12
    I think everyone's tried to find out
  738. 00:29:16
    which one's going to get you to your
  739. 00:29:17
    goal faster. But a lot of these
  740. 00:29:20
    patients, as Andy alluded to in the
  741. 00:29:22
    beginning, we don't really know what is
  742. 00:29:25
    the ideal systolic blood pressure for
  743. 00:29:28
    these patients. So I think that's what
  744. 00:29:31
    kind of complicates answering this
  745. 00:29:33
    question because
  746. 00:29:37
    the numbers are so different in each
  747. 00:29:39
    patient. I think clinical outcomes are
  748. 00:29:43
    probably the most meaningful, but
  749. 00:29:45
    there's
  750. 00:29:48
    so much that these patients, the
  751. 00:29:50
    changes, how are you going to, at what
  752. 00:29:53
    point do you look at those clinical
  753. 00:29:54
    outcomes? Hematoma expansion, maybe,
  754. 00:29:56
    is this like a good marker? There's
  755. 00:29:59
    good markers, but
  756. 00:30:02
    I don't know. Andy, what do you think?
  757. 00:30:04
    Yeah, so I think there's a couple of
  758. 00:30:06
    things that are just like perennially
  759. 00:30:08
    missing in every single. single center
  760. 00:30:11
    retrospective study that's looked at
  761. 00:30:13
    this. And I think even if it wasn't
  762. 00:30:16
    asking for the million dollar grant for
  763. 00:30:18
    that dream RCT that's never going to
  764. 00:30:20
    happen, I think one thing that would be
  765. 00:30:23
    nice in the next single center
  766. 00:30:25
    retrospective study that's inevitably
  767. 00:30:27
    going to come out is how are centers
  768. 00:30:29
    actually using the drugs, right? And
  769. 00:30:31
    so there's at least six or seven studies
  770. 00:30:34
    that have looked at time to goal between
  771. 00:30:37
    my cardopene and clivettapene. And all
  772. 00:30:39
    of the studies describe how their center
  773. 00:30:42
    recommends the doses are titrated and
  774. 00:30:44
    they're all within packages or
  775. 00:30:45
    recommendations. Several of them
  776. 00:30:46
    suggest that they're actually doubling
  777. 00:30:48
    the dose every time the clivettapene
  778. 00:30:55
    dose every time is eligible for
  779. 00:31:00
    titration, which is fantastic. But
  780. 00:31:00
    none of the studies report whether or
  781. 00:31:00
    not that actually happens. And so it's
  782. 00:31:00
    really challenging to assess the
  783. 00:31:00
    differences in these time to therapy or
  784. 00:31:02
    time to cisdog blood pressure goal,
  785. 00:31:04
    because there's no way of knowing how
  786. 00:31:05
    the drugs are actually used. A few of
  787. 00:31:07
    the studies actually report doses. A
  788. 00:31:08
    lot of times it's really just like a
  789. 00:31:10
    straight cost analysis or a volume
  790. 00:31:11
    analysis. And so I think honestly, the
  791. 00:31:14
    simplest study to do that would really
  792. 00:31:16
    help address this question is, we all
  793. 00:31:18
    talk about the theoretical
  794. 00:31:19
    pharmacokinetic benefits, but does that
  795. 00:31:22
    actually translate to clinical practice
  796. 00:31:23
    if you're using it in the way it could
  797. 00:31:25
    be used? Or is it just being used in
  798. 00:31:27
    the way that night card is being used?
  799. 00:31:29
    And so I think the great way to look at
  800. 00:31:31
    this is basically like how many dose
  801. 00:31:33
    titrations were required to date your
  802. 00:31:35
    goal independent of time and how quickly
  803. 00:31:38
    in between each dose titration were
  804. 00:31:40
    nursing or staff able to kind of make
  805. 00:31:42
    those changes. So I think that would be
  806. 00:31:44
    a huge thing to just help put to bed
  807. 00:31:46
    like, can we even use clavitapine in
  808. 00:31:50
    the way that it is intended to be used?
  809. 00:31:52
    So I think if it turns out that, in a
  810. 00:31:54
    huge population of neuro-critical
  811. 00:31:56
    patients, everybody's clavitapine is
  812. 00:31:58
    titrated every 30 minutes, then it's
  813. 00:32:00
    like, what's the point? But then
  814. 00:32:01
    there's really no difference no
  815. 00:32:02
    advantage to using a drug if we can't
  816. 00:32:05
    use it in that way. And then obviously
  817. 00:32:06
    I think the bigger thing would be, yeah,
  818. 00:32:08
    is more rapid control associated with
  819. 00:32:11
    reductions in hematoma expansion. Is
  820. 00:32:14
    the time to blood pressure goal lowering
  821. 00:32:16
    associated with better functional
  822. 00:32:17
    outcomes? Like I think some of the
  823. 00:32:19
    interact three data will be really
  824. 00:32:21
    interesting. 'Cause if you like dig
  825. 00:32:23
    into the supplement of interact three,
  826. 00:32:25
    like how they used meds is like a little
  827. 00:32:28
    interesting, at least my biased, you
  828. 00:32:31
    know, Northeast United States academic
  829. 00:32:33
    practice, right? Recognizing the
  830. 00:32:34
    different settings that the study was
  831. 00:32:36
    done in. But what I hope we'll be able
  832. 00:32:39
    to see with interact three, if they end
  833. 00:32:40
    up doing some post hoc analyses is
  834. 00:32:43
    whether or not there are actually
  835. 00:32:44
    differences in the agents that were used,
  836. 00:32:46
    which hopefully we'll be able to
  837. 00:32:47
    additionally address some of these
  838. 00:32:48
    questions. So yeah, I think that like
  839. 00:32:51
    we have a decent amount of data and
  840. 00:32:53
    overall retrospectively, it doesn't
  841. 00:32:55
    seem there's huge differences between
  842. 00:32:56
    the two drugs. But the major things
  843. 00:32:58
    that are missing is how we're using them.
  844. 00:33:00
    And I think that's the main thing that
  845. 00:33:01
    would help to answer the question.
  846. 00:33:04
    Is there any data on rates of
  847. 00:33:05
    overshooting blood pressure control and
  848. 00:33:07
    whether that kind of results in some
  849. 00:33:09
    safety concerns for the two drugs? Yeah,
  850. 00:33:13
    so most of the retrospective studies do
  851. 00:33:15
    report either rates of hypotension or
  852. 00:33:19
    rebound hypertension, and by and large
  853. 00:33:22
    rates of hypotension are not
  854. 00:33:24
    significantly different in most of the
  855. 00:33:25
    studies, but that is limited by small
  856. 00:33:27
    sample sizes. And so, you know, I
  857. 00:33:29
    think the biggest retrospective study
  858. 00:33:31
    looked at maybe about 100 to 200
  859. 00:33:33
    patients, so it's kind of hard to find
  860. 00:33:35
    those relatively rare events. But in
  861. 00:33:37
    terms of significant hypotension,
  862. 00:33:40
    probably somewhere between 5 and 10 is
  863. 00:33:42
    average across most of these studies,
  864. 00:33:44
    and I think there's at least one study
  865. 00:33:46
    that showed the only patients that
  866. 00:33:47
    actually needed intervention were the
  867. 00:33:48
    ones that were on NICARD, which may be
  868. 00:33:50
    explained by the longer half-life,
  869. 00:33:51
    where if you overshoot, you're going to
  870. 00:33:52
    be dealing with the consequences for a
  871. 00:33:54
    couple of hours. But one interesting
  872. 00:33:55
    thing is there is a paper that was
  873. 00:33:57
    published in neurocritical care last
  874. 00:33:58
    year that did show that there was
  875. 00:34:00
    significantly higher rates of rebound
  876. 00:34:02
    hypertension in the And I know I'm
  877. 00:34:04
    supposed to be arguing pro clovidopine,
  878. 00:34:06
    but I feel like I'm obligated to point
  879. 00:34:07
    that out. We appreciate your honesty.
  880. 00:34:12
    That's actually a, maybe this is a good
  881. 00:34:14
    time to unzip those team jerseys and
  882. 00:34:17
    just sort of take off your
  883. 00:34:20
    clovidopine and nycardopine jerseys and
  884. 00:34:22
    put on your regular pharmacist hats. I
  885. 00:34:25
    wonder, like, what are your real
  886. 00:34:26
    thoughts now that we've kind of gone
  887. 00:34:28
    over the big concerns in the data and
  888. 00:34:32
    what, if you were in charge of the use
  889. 00:34:35
    of clovidopine and nycardopine in your
  890. 00:34:37
    hospitals, like, what would you be
  891. 00:34:38
    recommending? And maybe we'll start
  892. 00:34:41
    with you, Colleen.
  893. 00:34:43
    Yeah, I think it's a great question.
  894. 00:34:45
    And as I alluded to in the beginning,
  895. 00:34:46
    this is something that we don't have in
  896. 00:34:48
    our shop. So there is a little bit of -
  897. 00:34:50
    I'd like to drive that new fancy car and
  898. 00:34:53
    see how it works and see what everyone
  899. 00:34:55
    else is talking about
  900. 00:34:59
    But, you know, I think that while the
  901. 00:35:01
    data is hard to capture. I think it's
  902. 00:35:05
    hard to go full force for COVID in a
  903. 00:35:10
    pain while the data is not there for
  904. 00:35:14
    finding that difference. In clinical
  905. 00:35:16
    practice, even the time to get to that
  906. 00:35:20
    goal systolic blood pressure varies in
  907. 00:35:22
    these retrospective studies. Some of
  908. 00:35:23
    them list 30 minutes, 45 minutes for
  909. 00:35:26
    each of these agents, and the one that
  910. 00:35:28
    Andy alluded to, and the nicartic has
  911. 00:35:30
    to come from the pharmacy notes in an
  912. 00:35:32
    hour and a half
  913. 00:35:35
    So, it's something that I think if I
  914. 00:35:37
    saw in clinical practice a faster time
  915. 00:35:42
    to goal systolic blood pressure, I'd be
  916. 00:35:45
    more willing to shell out the money for
  917. 00:35:47
    the brand new car.
  918. 00:35:51
    Okay, Andy? Yeah, honestly, I
  919. 00:35:54
    personally am much the same, where I
  920. 00:35:56
    think that this is a great example of
  921. 00:35:59
    the difference between a population and
  922. 00:36:02
    an individual where At the population
  923. 00:36:05
    level, you know, we have six or seven,
  924. 00:36:07
    you know, they're all have their flaws,
  925. 00:36:09
    of course, but you know, single center
  926. 00:36:11
    reasonably well done retrospective
  927. 00:36:13
    studies that look at overall in a
  928. 00:36:16
    general stroke population, including
  929. 00:36:19
    ischemic, hemorrhagic, subarachnoid
  930. 00:36:20
    strokes with varied goals. They're all
  931. 00:36:24
    over the place, high and large. The
  932. 00:36:26
    difference in time to goal attainment,
  933. 00:36:28
    assuming you subtract the time that it
  934. 00:36:31
    might take the pharmacy to compound the
  935. 00:36:34
    nichardopene, they're not really that
  936. 00:36:34
    different. And so I think that probably
  937. 00:36:37
    speaks to the clovidopene just not being
  938. 00:36:40
    used in a way that it could be used,
  939. 00:36:43
    'cause at least in the two prospective
  940. 00:36:44
    studies in this population, so
  941. 00:36:46
    accelerate, which was in spontaneous
  942. 00:36:47
    ICH and then the clash trial, which was
  943. 00:36:50
    a tiny pilot trial in subarachnoid
  944. 00:36:52
    hemorrhage. And those two studies,
  945. 00:36:54
    when they did intentionally use
  946. 00:36:56
    clovidopene in the way that it was
  947. 00:36:57
    intended to be used, you did see faster
  948. 00:37:00
    time to goal And so I think my kind of
  949. 00:37:02
    takeaway. between those two disparate
  950. 00:37:06
    conclusions is that in your average
  951. 00:37:08
    patient who needs a continuous infusion
  952. 00:37:11
    to get good blood pressure control,
  953. 00:37:14
    nichardopine works just fine. It gets
  954. 00:37:16
    you to your goal in a reasonable amount
  955. 00:37:17
    of time. It's familiar. It's generally
  956. 00:37:19
    pretty reliable. And most people know
  957. 00:37:23
    how to use it, know how to titrate it.
  958. 00:37:25
    Interestingly, at MGH, we don't have
  959. 00:37:28
    the premixes, but we actually stock the
  960. 00:37:30
    vials in our dispensing cabinet and
  961. 00:37:32
    nurses snap it together with the mini
  962. 00:37:35
    bag plus vial. So we kind of have the
  963. 00:37:36
    best of both worlds, where we have the
  964. 00:37:38
    cost savings of the generic vials, but
  965. 00:37:40
    the ready availability of it being on
  966. 00:37:42
    the unit. And so we are kind of in a
  967. 00:37:45
    luxurious spot where both are equally
  968. 00:37:47
    available. But if you're say, like
  969. 00:37:51
    this has happened a handful of times or
  970. 00:37:53
    say somebody is in the emergency
  971. 00:37:55
    department and they get to next the
  972. 00:37:56
    place and everything's going great. And
  973. 00:38:00
    then in the hour two or hour three
  974. 00:38:02
    neurocheck, there's a dramatic change.
  975. 00:38:04
    And so everybody rushes to the scanner
  976. 00:38:05
    or the patient and they have this big
  977. 00:38:07
    bleed. And it's a true all hands on
  978. 00:38:09
    deck scenario of who's gonna get the
  979. 00:38:11
    cryo, who's gonna get the TXA, who's
  980. 00:38:13
    gonna get the blood pressure meds. In
  981. 00:38:15
    those sorts of scenarios where there's a
  982. 00:38:16
    lot of resource available to kind of
  983. 00:38:18
    have every single piece in place, I do
  984. 00:38:22
    like Clivita P. Moore. Because in that
  985. 00:38:24
    scenario, oftentimes I could be the one
  986. 00:38:26
    at the pump and they may already have,
  987. 00:38:28
    if they're probably recycling blood
  988. 00:38:29
    pressure frequently or you know, if
  989. 00:38:30
    you're really lucky and they have an A
  990. 00:38:32
    line for whatever reason, you can
  991. 00:38:34
    titrate it rapidly to get control, but
  992. 00:38:37
    only if you kind of have the capability
  993. 00:38:39
    and the time to do that. And so I think
  994. 00:38:41
    like my personal practice is that like
  995. 00:38:44
    our first line continuous infusion for
  996. 00:38:46
    your average patient is going to be an
  997. 00:38:47
    Icardipine, but there are definitely
  998. 00:38:49
    instances where I do believe that
  999. 00:38:52
    Clivita P. has an edge, but only if
  1000. 00:38:54
    you use it, right?
  1001. 00:38:56
    So I'm hearing that clovidopine should
  1002. 00:38:58
    come with its own little pharmacist
  1003. 00:39:01
    directing all the titration. I love it.
  1004. 00:39:05
    I wish that each one of our clovey
  1005. 00:39:07
    bottles came with a PI of a study or a
  1006. 00:39:10
    pharmacist to direct rapid titration.
  1007. 00:39:14
    Well, I want to really thank both of
  1008. 00:39:15
    you for your time and your incredible
  1009. 00:39:17
    expertise on this topic. I loved
  1010. 00:39:21
    hearing about your sort of real life
  1011. 00:39:23
    experience with these medications But
  1012. 00:39:27
    your, both your knowledge of the
  1013. 00:39:28
    literature is really impressive. So
  1014. 00:39:31
    thank you so much to both of you for
  1015. 00:39:33
    your time. And I can't wait to hear
  1016. 00:39:37
    this debate in a couple of years, see
  1017. 00:39:40
    what's been happening at both your
  1018. 00:39:41
    institutions. Yeah, thank you so much
  1019. 00:39:43
    for inviting us on. Yeah, thanks.