CEimpact Podcast

COX-2 Inhibitors to Increase Effectiveness of Emergency Contraception

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Emergency contraception use has an effectiveness of about 70%. Join host, Geoff Wall, as he reviews new literature to see if COX-2 inhibition improves that rate.
 
The GameChanger
Emergency contraception (EC) is safe and effective but overall efficacy rates could be better. COX-2 inhibitors may enhance the effectiveness of EC but require multiday dosing.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial. Lancet. 2023 Sep 9;402(10405):851-858. doi: 10.1016/S0140-6736(23)01240-0. Epub 2023 Aug 16. Erratum in: Lancet. 2023 Sep 9;402(10405):850. PMID: 37597523.
https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(23)01240-0.pdf
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Describe the selection of the particular COX-2 medication used in this study
2. Discuss the implications of the COX-2 augmentation with patients

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-322-H01-P
Initial release date: 10/9/2023
Expiration date: 10/9/2024
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome to Game Changers clinical conversations. I'm your host, jeff Wall, professor of pharmacy practice at Drake University Today, again a little bit off the beaten path of what we usually talk about, but it was a fascinating paper that just got published in the Lancet a couple of weeks ago, that looked at emergency contraception and looking at what in the United States is called Plan B levonogesterole and looking at the addition of a non-steroidal to improve the efficacy of it. And when I read that byline I was kind of like what? But again, this is an area that certainly not an area of expertise of mine, so I did some reading on this. I was kind of surprised about that.

Speaker 2:

So before we get into this again, I really want to sidestep all the politics associated with emergency contraception. We're going to talk a little bit today about the incidence and how much the increase of use of EC has been in the last several years and we're going to talk a little bit about how it works. Again, not so much because I don't think the listeners understand, but because when patients are talking to you or patients are approaching, for example, a community pharmacist at asking for this and they have questions, I think knowing about this is kind of important. So again, let's hopefully can dodge any politics or the pro or con from other reasons. We're just going to talk about the efficacy of emergency contraception to prevent unwanted pregnancy after unprotected sexual intercourse, sexual assault or other recognized contraceptive failure such as a condom breakage or something along those lines. So that's what we're going to focus on the paper that was in the last it was done in Hong Kong, and we're going to talk about some of the pros and cons about that as we come along here. Again, looking at the kind of statistics of it, it's kind of interesting. We've had emergency contraceptives, in particular plan B, in the United States for over 20 years and if you take a look at the stats associated, up to 2019, we had 28% of women ages 15 to 44 who had ever had sex with a male had reported use of emergency contraception at least once in their lives. I'll be honest, that was a far higher number than I would have expected, but that number is, of course, higher than when it first came out in the early 2000s, where it was only 4%. So I think, as people have become more aware of this and they know that this is an option, it's certainly been used more, I think, as we become more aware of the safety associated with this. That's been good as well. As you might imagine, it's mostly younger women who tend to report its use and if you take a look at cohorts, in general it depends on different ethnicities.

Speaker 2:

But bottom line is the use of oral emergency contraception is again more common than I certainly thought In the United States. Plan B is a single dose of 1.5 milligrams levonogestero which is taken within 72 hours of unprotected sexual intercourse. There are some other ones as well, the little pristyle acetate, which is given within 120 hours of unprotected sexual intercourse, but Plan B is certainly the most common one you're going to see. Remember that emergency contraception is only effective when given before but not after ovulation, and because it works by preventing pregnancy, by blocking or postponing luteinizing hormone surge, thus disrupting the ovulatory process. But its effect is limited to its administration before the onset of luteinizing hormone surge, but not after that has occurred. And so of course, that's why you have the kind of the time factor, because at that point it's when intercourse is happening. Doing the luteinizing hormone surge is when pregnancy is most likely to result. So how this medication works is that it basically lowers the ability to block ovulation and prevent fertilization Once the ovulatory process has been triggered by luteinizing surges. It really can't work at that point. So the bottom line is that you know again, without getting too much into the weeds about this, it is not an abortive phase and it basically just helps prevent this luteinizing hormone surge and basically kind of interrupts the ovulatory process. It has no effect on sperm function, fertilization or implantation, so let's kind of get that out of the way. So the big question mark here, of course, is non-seroidals help with this, and I wouldn't have thought that so, though the studies show that, of course, prostaglandins do facilitate several reproductive processes, including ovulation, fertilization, tubal function and embryo implantation.

Speaker 2:

It has been thought for a long time that it's possible that blockade of a coxenzyme might actually act at least synergistically with oral and emergency contraceptive methods, and there have been some pre-clinical studies that had suggested that. You know studies in animals and stuff that has suggested that it did work, not by itself, which, of course, that kind of stands to reason, but working with emergency contraceptive hormonal methods to increase its efficacy. Several of the previous smaller previous studies have been published taking a look at this, and there was actually a 2016, 2016 analysis that looked at all this and basically found that the data was kind of inconclusive, largely because they use different non-seroidals, things like melcoxam, selicoxib, which are, you know, of course, more specific cox2 inhibitors, and the numbers are really small. So, again, the data was kind of inconclusive. The other piece of this, of course, is that all those drugs have relatively short half-lives, so you can't just take one dose with the leave and adjustorial. You can't actually take it for several days after, and that is, you know, that's requiring on adherence, which again may result poor compliance and decreased efficacy. So this study that came out of Hong Kong said, well, yeah, previous studies, they were all small, they used different nonsteroidals. We're going to try and do a larger study. That kind of answers this question once and for all. And so it was a randomized, double blind, placebo controlled study and they wanted to look at peroxacam.

Speaker 2:

Now, peroxacam, if you're an old man like me, was one of the old, old, old nonsteroidals that was even hardly barely used when I came out of pharmacy school painfully about three decades ago. It was hardly used back then and certainly I haven't seen used in over 20 years now. The reason why is that? It because it's a little more Cox 1 selective than Cox 2, it was always known to have a higher incidence of gastric ulcers, acute kidney injury and stuff like that. So in the United States I haven't seen it in 20 years. I had to do a little research.

Speaker 2:

It looks like it is still available in the US, but I think availability in individual pharmacies may be a challenge. I'm sure there's only a couple of companies that still make this medication. So cost might be an issue, even though it's been a long generic issue, et cetera, et cetera along those. It may be difficult to replicate this in the United States just because peroxacam, even though it's a way old nonsteroidal, may be difficult to get, just because nobody really uses it anymore. But they picked it because of its really really long half life. Its half life is far longer than standard nonsteroidals that are used in practice. So you would be able to use a single dose of this medication. So that would help with compliance and, of course, quite frankly, help them be able to do the study, because they only have to give a single dose of the peroxacam with the 40 milligrams of lima gestril. So that's how the study was set up.

Speaker 2:

Again, it was an RCT that was done in Hong Kong, conducted by the Family Planning Association, which is, from what I've read in Hong Kong, one of the big kind of Planned Parenthood analogs in Hong Kong that helps provide sexual and reproductive health services. Basically they included people in the study if they had several criteria. First, they had to be healthy in over age 18. Second, they had to request emergency contraception within 72 hours. So emergency contraception in Hong Kong is kind of a behind-the-counter status where they can ask their pharmacist for it and then basically if they meet criteria they get it. So I had requests within 72 hours after a single act of unprotected sexual intercourse in the current menstrual cycle. Third, they had to have fairly regular menstrual cycles between 24 and 42 days long. Fourth, they had to agree to abstain from further acts of unprotected sexual intercourse. And fifth, they had to agree to be available for follow-up so they could take a look at the outcomes.

Speaker 2:

Exclusion criteria included current pregnancy, which would make sense, or breastfeeding, being post-abortion or postpartum and not yet having resumed menstruation if they have kind of irregular periods and really weren't sure when their last menstrual period had started and ended. If they had an IUD placed or had been either previously sterilized or reporting having a partner being sterilized would kind of make sense as well. Those who reported having used hormonal contraception in the current or previous menstrual cycle. And here is where I think it's going to be a difficulty in the generalization of the study because they excluded, I think, a fairly large percentage of patients who would probably use plan B in the United States, who are women who are taking oral contraceptive pills and either forgot a pill or something along those lines that would make them want to select emergency contraception basically.

Speaker 2:

So that's kind of a little bit tricky if they were taking non-sportills in the previous week and so again that would make things a little tricky because who might not have taken ibuprofen for a headache or something like that in the previous week as well? And then basically, a lot of kind of more esoteric stuff. They couldn't currently be on anticoagulants or any medication which would interact with non-steroidals or a drug that would make them more likely to bleed, so like they couldn't be on, like I said, anticoagulants or lithium or things along those lines.

Speaker 2:

If they had any history of allergy, they of course were excluded as well. Finally, and who reported a history of asthma, urticaria, ischemic heart disease, heart failure, septic ulcer disease, I mean basically anything that a non-steroidal might exacerbate, were all excluded. I don't think that's that big of a deal because I think the population that's primarily gonna use this I think tend to be relatively healthy. So I think, again, a single dose of proxscam is probably unlikely to have any serious adverse offense that you would expect with non-steroids. At least that's my thought on that. As far as the study, they basically had both pills compounded. Basically the placebo pills were specifically made by the hilariously named unicorn laboratories in Hong Kong. Now, that's a lab I wanna work for is unicorn laboratories but basically they made sure that all the pills basically looked exactly the same.

Speaker 2:

Medications were prepackaged as drug A and B and then the patients were randomized to receive, you know, group A, which had the emergency contraception, and one dose of peroxacam, and the packet that said drug B was the emergency contraception and placebo. Basically, when they were recruited in the study they had to have a negative pregnancy test at baseline makes sense and again they received a single dose of a levonogestral 1.5 milligrams together, peroxacam or just levonogestral by itself. Basically the medications were administered under direct supervision, so that's kind of as good as well. They were then given a diary to measure average drug reactions and timing of return to menses. The primary efficacy outcome was the percentage of pregnancies prevented, as calculated by what's called the Trussell's model, and apparently this is a standardized way to estimate contraceptive effectiveness. It basically looks at the total number of pregnancies per group, as calculated as the average number of expected pregnancies multiplied by the number of efficacy of valuable participants in the group, and then it basically takes a look at what you would expect to be pregnancies, based on where in the menstrual cycle they are compared to what actually happened in the study. So kind of interesting and apparently this is relatively common in contraceptive studies, looking at efficacy. So I had not seen that before. I'd done a little research on it basically. So this was the primary outcome.

Speaker 2:

They also looked at several secondary outcomes, including the date and return of menses. They looked at occurrence of non-menstrual bleeding and then other adverse effects such as nausea, vomiting, things along those lines. They interestingly, in the study design did not do a data invitation for missing data, so they didn't do like last observation carried forward, I'm not really sure if that's a good thing or not, because if you don't have really good follow up, if you have to kind of make the assumption whether they, if we lost them to follow up, did they actually become pregnant or not. So this is the kind of study where I think last observation carried forward may not necessarily be the best way to conduct the study, but that's kind of what they did. As far as power is concerned, they wanted to make sure they had enough patients because, again, all the other previous studies had relatively low numbers. Doing their power calculations, they wanted to look to see that at least a 10% increase in efficacy, which is considered clinically meaningful, would have to be targeted, and so they actually had a number of 860 patients in the study, again far larger than previous studies.

Speaker 2:

Looking at this, statistics were pretty standard. Again, nothing really bizarre. They used Chi-squared test, logistic regression, but interestingly they did do a couple of subgroup analyses. One was they wanted to look at pre-obulatory versus post-obulatory, at the time of emergency contraception, and they did that by drawing levels of luteinizing hormone and progesterone and things along those lines to help classify that. And then the second subgroup was body weight and again, this is, as you might imagine, going to be one of the big generalization problems between a study done in Hong Kong and US patients. And so they used a cutoff of a BMI of 26, or a body weight of 70 kilograms, and they wanted to look at subgroup analysis to see if it was more effective in the first or the second group. So what were these patients, what did they find and what are the implications, I think, for using emergency contraception? We're going to talk about that right after a message from our sponsor, ce Impact.

Speaker 1:

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Speaker 2:

So we are looking at an interesting study published in the Lancet and as always we'll have the link to the study in our show notes that looked at adding peroxacam to plan B to see if it increases the effectiveness of emergency contraception Again a study done in Hong Kong. Taking a look at the study itself and the baseline characteristics Average age was 31 in the study, and then here's going to be one of the things I think we have to talk about is a mean weight was 54 kilograms and so body mass index in this study was 21, which again I think may hamper some of the generalizability. Only about 10% of patients in the study actually had weights over 70 kilograms or had a BMI greater than 26. So take that for what you will. As far as ethnicity, the overwhelming number of patients were Chinese, as you might imagine from a study out in Hong Kong. So time from intercourse to being enrolled and being in the study was 18 hours. I think pretty good there. And again, you know, you know, keeping in mind that these patients were pretty much seen right away and giving emergency contraception right away, About 40% of both patients, both arms, had been pregnant previously, with about 31% given birth in patients, so about a third of these patients had given birth previously. So for emergency contraception, the overwhelming number of reasons was condom failure, though there were some other numbers as well. So then we use this trussles method to kind of figure out the objective versus observed.

Speaker 2:

So looking at this patient, this cohort, looking at when they could have expected to be pregnant in the placebo group, they figured that the observed rate of pregnancy and again this was just in patients who received the emergency contraception was 1.7%. So 1.7% is what they would, what they actually saw as far as people who were just on the limo digestural. When they added paroxicam it actually dropped to 0.2%. Now you may say, well, that's not that big of a deal, but the expected pregnancy is really kind of tells the tale here. So the expected pregnancy rate would be 19%. So if the patients weren't taking emergency contraception at all, the expected pregnancy rate would be about 4.6%. So what that means then is if in just the emergency contraceptive group you go from 1.6%, 4.6% to 1.7%, and in the paroxicam group and plan B you go from 4.6% to 0.2%. So if you add all that up, the proportion of pregnancies prevented in the just the limo digestural group was about 65% and the proportion of pregnancies prevented in the paroxicam group was 95%, so significantly higher than they even estimated in their power calculations, as you might, as you might imagine, that was very statistically significant. So you know, again, the numbers themselves may not seem all that high but again, taking a look at this, it dramatically increased the proportion of pregnancies prevented in the study. So you know, that seemed to be pretty effective there.

Speaker 2:

As far as average drug reactions, they actually didn't find that much of a difference between the two groups. There was no difference in stomach issues or nausea and vomiting, stomach pain, things along those lines. In the sample they had, they know that there was a very small percentage of patients who had a BMI of over 26. And they noted that that no group in either category were pregnant in this category. So again, that does make me a little nervous about about, you know, blanket recommending this combination Because unfortunately in this study the number of patients with a BMI over 26 was so small and none of them became pregnant in either group, it becomes very difficult to extrapolate the overall data to women who might, might have higher BMI.

Speaker 2:

So that's just worth noting. I think about 138 women agreed to have the blood taken for hormonal assays. So even though they wanted to take a look at pre versus post ovulation, they had such a small number of patients that they basically abandoned that and said they decided not to do it. So overall it seemed to be about equally well tolerated. There didn't seem to be any significant increase in side effects, return of men's.

Speaker 2:

These was actually similar between groups as well. So again, nothing along those lines. And again, an increase of proportion of pregnancies prevented, that again, I would say about 25%. So you know, the authors comment that it seemed to be, you know, associated with an increased risk of or increased efficacy at preventing pregnancies, but not an increased risk of adverse drug reactions, including no disturbances to menstrual patterns. They do note, again, as we've talked about in the pod, that there were several generalizability issues. Again, most of these patients were had a BMI below 26. So again, that might be difficult to translate. They also note that they excluded patients who had current hormonal contraception and again, I think that's going to be going to be a little bit tricky, especially in places like the United States where oral contraception is actually pretty common. So I think that's you know, those are some issues which I think are may limit the generalizability of this data, but I'm not sure a bigger study is ever going to be done in this.

Speaker 2:

I'm kind of dismayed that again they did not include patients, women, who are on hormonal contraception, just because, again, that's so common in most of the western world. You know, I, looking at the population, I'm not really surprised at an overall lower number of patients who were obese. And so, again, we know that obesity decreases the efficacy of emergency contraception and that makes things a little bit difficult as well. But I mean, I'm hoping that this might be a nice baseline to actually take a look at this combination use, if for no other reason, in patients who do fit the parameters of the study. So if you had a patient who wanted emergency contraception, was not currently on hormone contraception and again required or would like emergency contraception because of condom failure or something like that, and especially if their VMI is less than 26, I think that this data is pretty compelling and, I think, pretty strong and a pretty well done study. So the question becomes how does this happen? Emergency contraception can be basically requested, whereas paroxycham would require a prescription. So that's gonna make things a little tricky. In the United States Do you have separate pills that you give at one time? Will some ambitious drug company decide based on this, they'll come up with some sort of combo pill that you take at one time that, of course, they can charge a million dollars for? I hope not, but that certainly I can see that possibility occurring as well. So I think the bottom line is it's a fascinating study and I think it proves for the first time that adding non-steroidals does seem to enhance the efficacy of emergency contraception. Now the implementation becomes the hard part. And how can we translate this, especially in the United States, to the patients, I think, who fit the parameters of the study, as well as making it as convenient as possible? We know that convenience and ease of access is one of the key factors in using emergency contraception and, while I'm all I'm very interested in these outcomes, if anything adds significant barriers to accessing emergency contraception and decreases uptake by the women who would like to have it, that becomes, I think, somewhat problematic in trying to apply this data, especially in the United States.

Speaker 2:

So that's it for this week of Game Changers. Thanks for listening again. That's it for this week. I do want to mention that many of you know I'm a producer of house music under the name Prophet of Jupiter and I was very fortunate to have a couple of singles released on the Electric Eden house label. You can actually listen to that anywhere you get music, so Spotify, youtube, apple Music, et cetera, et cetera. Please give it a listen and see what you think and shoot me an email if you like what you hear. Anyway, we'll see you next week. Remember, the time flies. I don't know where it's going, but the most important day is today. We'll see you then.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on Game Changers Clinical Conversations.