Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 55 I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel, and the title of this episode is, how low can you go blood pressure Limbo with Sprint. We'll be talking about the SPRINT trial and using a clinical case vignette to kind of introduce the clinical conundrum of how low should you target for a blood pressure goal for a patient? Dr. Khyati Patel 00:52 All right, so let's see what we have today. Mr. Wilson, a 55 year old male patient with a blood pressure of 139 systolic and 89 of diastolic. Who's on Lisinopril, 20 milligrams daily. He is currently smoking no coronary artery disease. He does not have diabetes. His lipid panel is fairly good, and he doesn't have any other past medical history. And that gives us his Framingham, the 10 year risk score to be about 18% Dr. Sean Kane 01:20 just to touch on his Framingham risk very briefly, one of the main factors that this patient, Mr. Wilson, has is his age in terms of what contributes to his Framingham risk, and that's obviously a non modifiable risk factor. In terms of modifiable risk factors, the big one here is going to be smoking cessation. So for now, we'll kind of put that away, because we're really trying to focus on blood pressure. And blood pressure is the other modifiable risk factor that Mr. Wilson has. Speaker 1 01:44 But overall, looking at JNC eight, some of what the standard we've been going by as far as blood pressure, his blood pressure is actually at the JNC eight goal of less than 140 over 90. So the question there is, should we pursue a more aggressive blood pressure goal? And this is question that a lot of individuals have been asking over over the last few years, and it was answered by the SPRINT trial, which was published in November of 2015 so the community overall has had a year to kind of chew on the results of it, offer some feedback on it. And now where we're at here. We were still answering, you know, what does it say now? Where's the clinical picture a year later? And how should we treat Mr. Wilson's blood pressure or similar individuals moving forward. Dr. Sean Kane 02:22 Yeah. So kind of the goal of this episode is to talk about the SPRINT trial and then go back to Mr. Wilson and say, do we have adequate data to say that we should be more aggressive with Mr. Wilson's blood pressure control? So just for background on the SPRINT trial, sprint is an acronym for systolic blood pressure intervention trial, and basically it compared to blood pressure goals, a more aggressive, less than 120 systolic, or less aggressive, less than 140 systolic among non diabetic patients. And that's one key element there is the non diabetic patient. Speaker 1 02:52 And this was an open label study of over 9000 patients that were in it. So again, we've got a large, robust pile of data to pull Dr. Khyati Patel 02:59 from here and study pretty much included patients age was above 50, so systolic blood pressure was ranging anywhere between 130 to 180 and they had increased risk of cardiovascular event. And that kind of was described as any of the non‑stroke atherosclerotic cardiovascular disease (ASCVD). So some of the examples would be MI, peripheral arterial disease, or abdominal aortic aneurysm, if they had a chronic kidney disease with the GFR that was lower, as low as 20 to 60 Framingham risk score of greater than 15% and age greater than or equal to 75 which basically gave us majority of the patient being our elderly adult patient population. Dr. Sean Kane 03:47 So if we really have to kind of paint the picture of who's in the trial, we see older people who are not diabetic, who are at slightly higher risk for a cardiovascular event. Speaker 1 03:56 And like any study, you know, inclusion criteria is one thing. We also have to look into who is excluded. And one big point that I believe Dr. Kane already mentioned is the fact that individuals diagnosed with diabetes were excluded right off the bat. And so that was a huge amount of individuals there who are going to be by nature of diabetes, are going to have a lot of those other risk factors, but were not included. And really the decision was, there have been previous trials. So looking at one prior study, I found that in diabetics, more aggressive blood pressure goal did not find benefit, and so be drawing from that other data, they said, All right, we're going to go ahead and exclude those individuals from this study. But again, that took out a large population. Dr. Khyati Patel 04:35 And I believe that the trial that you're referring to is the Accord trial, which showed that, you know, intensive blood pressure control in patients with diabetes actually was harmful than the regular blood pressure control, and so I can almost lose my attention with the fact that patients with diabetes were not included, because most of my clinical practice is with patient with diabetes. But let's see what else was excluded as well. Speaker 1 05:00 So previous strokes were also excluded. End stage renal disease, so a GFR of less than 20, so again 20 to 60, but then less than 20 was cut out, and heart failure or low ejection fraction below 35% Dr. Sean Kane 05:13 and in terms of what they actually looked at, they had a composite endpoint of basically cardiovascular events. So either dying from a cardiovascular cause, having a heart attack, having a stroke, or having new heart failure, any of those qualified you as having the primary event for safety analysis. Obviously, we're worried about dropping a patient's blood pressure too low, especially among this elderly patient population. Clearly, the especially in the elderly, we're worried about falls, orthostasis, getting dizzy, just Frank hypotension, with very low blood pressure, numbers, electrolyte abnormalities, primarily from our diuretics. So they have a lot of safety endpoints related to basically a low blood pressure or side effects of some of the common BP meds that we use. So the Speaker 1 05:54 next thing to look at is what particular blood pressure treatment method was used in the study, and all the blood pressure regimens were adjusted according to a specific algorithm, and all the medications were provided for free with a general algorithm. Anyone with a compelling indication for a specific anti hypertensive class was given that agent. So for example, an individual who was post MI was able to receive a beta blocker, as opposed to just getting a general medication, like a one size fits all calcium channel blocker. But first line overall, if there was not a compelling indication, first line were diuretics, which is interesting, it was usually a thiazide, and then ACE or ARB or a calcium channel blocker. And regarding diuretics, specifically chlorthalidone was preferred in the study over hydrochlorothiazide, which is somewhat interesting. I believe in my practice, at least see much, much, much more hydrochlorothiazide within there. I don't know if either of you all can speak to that. Dr. Khyati Patel 06:48 Yeah, I've seen hydrochlorothiazide more so as well, not just in my clinic. But you know, when I used to work in a pharmacy, we saw more of those prescriptions versus chlorthalidone. And pointed out that, yes, chlorthalidone might be a little bit more effective in lowering the blood pressure than hydrochlorothiazide. With that more efficacy comes more side effects, such as electrolyte imbalances with chlorthalidone and if you're considering you know these generic prescriptions, being able to afford them if they're on a multiple medication regimen, hydrochlorothiazide is on the four‑dollar generic drug list for most pharmacies, versus chlorthalidone usually does not carry that list. So that's Speaker 1 07:25 going to be one point I believe, to look at, as we look at the applicability to a real world population, is for individuals who are maybe not getting that particular diuretic, is the data still as applicable? Other thing, just to point out, the preferred calcium channel blocker was Amlodipine within the study, and again, that's one fairly well used in my clinic for counts of channel blockers. Very, very rarely Am I seeing things like nifedipine, for example. Dr. Sean Kane 07:50 So essentially, when we think about something like the SPRINT trial, we want to make sure that we understand what kinds of drugs the patients received to treat their blood pressure. And part of the reason for that is that over the past couple decades, we've sometimes seen that for certain indications, a specific drug class, let's say, an ACE inhibitor, may be better than another antihypertensive class, depending on certain compelling reasons. And that's why, for example, we have beta blockers for heart failure. So it's good to see that in the SPRINT trial, regardless of what group you were given, whether you're more intensive or less intensive, the treatment regimen should have been fairly similar, as long as you qualified for blood pressure management therapy. Dr. Khyati Patel 08:28 If we kind of evaluate the results of the trial, as we mentioned earlier, about 9300 patients were evaluated over the period of about three years or so. The original plan period was five years, because the results were so good that the trial was ended early for its benefit. And so if we look at the mean age, as we talked about earlier, mostly older patients were included. The mean age was about 68 years. But then 28% of the patient in the in the study itself were above 75 years of age. Speaker 1 08:58 About 1/3 of the population was African American, which is fairly, fairly good compared to a lot of studies which have had difficulty in rolling that number, which then therefore makes it, again, hard to apply to the kind of population you may be seeing in the real world, about 1/3 were female, and at baseline, the mean blood pressure was 140 over 78 they were on a average of about 1.8 blood pressure medications, and Framingham risk was about 20% Dr. Sean Kane 09:24 so this really represents Mr. Wilson, the patient that we're talking about. He's on one blood pressure medicine. His blood pressure is right around the 140 over 80 mark, and he's at a slightly higher risk for cardiovascular disease. So in terms of the efficacy results at one year, as you would expect, we did see a difference in blood pressure, which was kind of the whole point of it. So we saw, if you were randomized to intensive therapy, your blood pressure was 121 on average for systolic versus 136 if you were randomized to the standard therapy, terms of number of meds given, clearly you're going to need more medicines to get your blood pressure lower. It was 2.8 medicines four. Blood pressure if you're on the intensive side, versus 1.8 which was kind of where they started anyway, for the standard therapy side. Speaker 1 10:07 Now looking at the other endpoint, so looking at the cardiovascular events, 1.65% when the intensive group versus 2.19% in this in the standard group. And so that ended up with a hazard ratio of point seven five and a statistically significant P value, Dr. Sean Kane 10:25 most of that difference, again, this is per year. Most of that was driven by heart failure and cardiovascular death. They did not see a difference in the individual endpoint of an MI or acute coronary syndrome or stroke, which is kind of what we would have assumed that we would see the benefit in as opposed to heart failure and cardiovascular death. So again, it was a composite endpoint. We like to look at the individual markers. Typically, when you look at the individual components of a composite, you're underpowered anyway. So it's not that it's a bad thing that we didn't show a benefit for these specific ones, but it was interesting that the main drivers of that composite were not what we thought it Speaker 1 11:00 would be. To its credit, though, it did also show an all cause mortality benefit with 3.3% within the intensive group, 4.5% per year and the standard group. And so again, hazard ratio point seven, three very similar, and again, a statistically significant P value. And let's just Dr. Sean Kane 11:15 think about those percentages for a second. So for if you're Mr. Wilson, if you're trying to describe the results of the SPRINT trial to Mr. Wilson within a one year period. And again, it ran a little bit longer than one year. But on a per year basis, we're basically talking about a major cardiovascular event of about, let's say, 1.6 versus 2.2% these are very rare things to happen to patients within that one year period. So really, for Mr. Wilson, if he's going to expect a benefit, he's going to have to have this more aggressive blood pressure lowering treatment for a long period of time in order for him to, statistically, or from a probability standpoint, really derive a benefit. Dr. Khyati Patel 11:50 Well, then you know, we're not only looking at efficacy results to decide whether we want to go that route of therapy, but we are also looking at safety results. So let's look at some of the safety issues that were considered in this trial, or were emerge as a result of this trial, and what we found we saw some renal impairment, and that was one point 21% in the intensive blood pressure control group, versus point three 5% in the standard blood pressure control group. Dr. Sean Kane 12:16 That's actually interesting, because typically when we think about hypertension, we associate hypertension with causing chronic kidney disease. In this case, it really emphasizes that if you go too low, the kidneys need blood pressure, and if you take too much blood pressure away from the kidney, you will cause blood pressure problems. It's kind of a U shaped curve. So even though oftentimes we're treating blood pressure to prevent CKD, we can actually cause at least acute kidney injury by being too aggressive with our blood pressure Dr. Khyati Patel 12:42 goal, yeah, and it could be because of the type of medicines that were used to lower the blood pressure. So we're talking about thiazides and ACE and ARB inhibitors, and we know that they they can easily cause renal injuries as well. Speaker 1 12:54 Another outcome so they looked at was, quote, serious ADR. I'll get to what serious meant in a second, but probably or definitely related to blood pressure medicines. What they found there again higher rates in the intensive group, 4.7% versus 2.5% hazard ratio, 1.88 and a significant P value there too. And when they said serious ADRs, it was again serious or those regarding an ER visit. And examples, there hypotension, significantly higher within the the intensive group. Syncope also significantly higher in the intensive group. Electrolyte abnormalities, mostly low sodium or low potassium due to the diuretics. Again, as Dr. Patel kind of alluded to, they have some of their own unique issues. Higher in the intensive group, acute kidney injury, higher injurious falls, though, was not different, and that's definitely a thing to look at, because that's one of the big concerns. When you think about if we overload this older individual on blood pressure medicines, are we gonna you know your blood pressure is lower, but hey, we've made you fall and hit your head, so if we really have you caught any better? Well, the fact here, it was 2.2% versus 2.3% and no difference, typically within the two. So that's actually a very interesting thing, and it's Dr. Khyati Patel 14:05 a little bit more comforting to see this result because we mentioned the basic patient population. Is that a lot of elderly patients were included in there. Dr. Sean Kane 14:14 And it's also important we forgot to mention this in sprint. They did not include patients in assisted living or long term care nursing homes. So these are not basically bed bound patients that are at very little risk for falls. These are ambulatory patients who aren't living, you know, an assisted living facility. They're on their own. Speaker 1 14:32 So as far as criticisms of the SPRINT trial, I know this is something that we like to look at. Are there any here? I mean, so far, it sounds, again, fairly well constructed. Dr. Sean Kane 14:40 So really, the big, interesting thing that came out over the past year is how blood pressures were measured in sprint, and this wasn't fully elucidated within the manuscript. And as you know, the year unfolded, this is one of the hot news items that has come up with Sprint. Dr. Khyati Patel 14:55 And so, I mean, I would assume that in a normal clinical practice, you know, a patient could. Comes in, maybe he's sitting out in the waiting area, gets checked into the room, and then the MA or the nurse will go ahead and check the blood pressure. So that time is about what five minutes, and sometimes their back's not supported. How exactly did the trial perform blood pressure screens here? Dr. Sean Kane 15:15 So what they did was they had the initial visit with the patient. The provider put on a blood pressure cuff that was automated. They left the room five minutes elapsed while the patient was in the room by themselves, and then the blood pressure cuff automatically measured their blood pressure three separate times with a one minute break in between. Really. The criticism there is that this isn't what we do in clinical practice. So the longer wait period no one being in the room during the blood pressure reading. The concern is that in the SPRINT trial, because they didn't have as much of a white coat syndrome is a 120 systolic blood pressure and sprint more representative of a 125 or 130 with white coat syndrome applied when you actually you know, see these patients in a clinic. Speaker 1 15:57 So again, that's something that makes you think you know. Perhaps Mr. Wilson here, his blood pressure of 139 over 89 would, on its own, go down to a lower blood pressure reading if we simply employed the techniques from Sprint and kind of incrementally over time as he relaxed, reassess the blood pressure. Or, for example, maybe we were to just check at the end of a clinic visit and say, oops, you've been sitting here for 30 minutes now maybe or more. Maybe you were nervous coming in, and now you're not nervous. Maybe we checked out. Maybe, on its own, it magically goes down. Dr. Khyati Patel 16:25 And then, you know, think about it, if you're trying to control it too aggressively to less than 120 like the trial suggests maybe it's too aggressive in terms of giving him more side effects. So is he willing to consider, or, you know, endure those side effects? That's another question, too. Dr. Sean Kane 16:39 And I think for me, one huge shake. Home point from this trial is the idea that maybe your blood pressure reading isn't as accurate as you think it is, and if you don't like the number very commonly in medicine, what we do is we just recheck it. Maybe that's probably the best thing to think about. Is if you would consider being more aggressive by giving a patient a chronic medicine for a long period of time, maybe a better strategy is, before making that decision, you do have that five or 10 minute break. You leave the room, you have someone else come in to just check the blood pressure in a very casual way. Maybe that does make a difference. Yeah. Dr. Khyati Patel 17:12 And I mean providing just an example from my regular clinical practices, I have patients tell me, you know, whenever I see a new provider, so I have new patients come in. They have not met me before. They don't know my style of practice, and you know, they're just nervous, you know, what's going to happen? Are they going to start me on another medication to control my diabetes or my blood pressure? You know? So all those questions are raging in their heads, and the fear of the unknown really does increase that blood pressure. But when they come during their second visit, third visit, become more familiar with that. You know, their blood pressure is a little bit better, and it literally shows that in the trend. Speaker 1 17:46 And then another thing again, to remind is that they excluded all patients with diabetes, and it's just some, you know, even though we do have the Accord trial, as Dr. Patel mentioned, just there's doesn't seem to be a clear reason why a lower blood pressure goal would work for non diabetics wouldn't work for diabetics. That's just something again, to make it to have to take the both of these, these study results, with a little grain of salt, just knowing that it there doesn't appear to be a kind of a rhyme or reason for that. Yeah. Dr. Khyati Patel 18:13 And it's interesting that you know SPRINT trial is a recent trial versus the Accord blood pressure arm was not very old, but it was older trial in itself. And I have a lot of physicians, even some of the patients, asking me that you know, whether they need to have their blood pressure control even to that extent. And my answer to them is, well, these patients were not studied in SPRINT trials, so we probably should refer to the older trials that were done in this patient population. And the other point to consider for this trial in particular, that the study included very old patient. I mean, mean age was 68 so these were, as you mentioned, we didn't find any falls. There were no differences between the fall risk between the two strategies. But these were the patients who were more ambulatory and were not residing into nursing homes or assisted living facilities. Speaker 1 19:02 And then, just to to be one more little nit picky point, the idea that the blood pressure, even in the intensive arm, it never truly went below 120 or at least not consistently, was just just above 120 couple ticks. You know, 121 21 122, so we're still somewhat in limbo as far as what exactly that blood pressure goal is that, you know, are we because, again, trying to reach 120 versus, you know, below 120 we're gonna have number of individuals, you know, maybe 110 112 115 so again, that wasn't what was done here. Dr. Sean Kane 19:30 So really, you're saying it was a trial of around 120 versus less than 140 as opposed to less than 120 versus less than 140 they basically kept patients around the 120 mark with some margin there. So really, you know, it's great that we have the SPRINT trial. It's great that we understand some of the criticisms and limitations of the SPRINT trial now that it's been out for a year, going back to our patient, which is really what matters. And you know, the whole point of analyzing the SPRINT trial is to figure out what to do in clinical practice. So what do you guys think we should. Do for Mr. Dr. Khyati Patel 20:00 Wilson. So if we remember from earlier, Mr. Wilson is a 55 year old gentleman who has a blood pressure of 139, over 89 and he's on less than a pill 20 milligrams. He doesn't have a cardiovascular condition. He doesn't have diabetes. His lipid is are reasonable, and his Framingham score is 18% so all that extra information tells me that he kind of falls under the ideal patient that were represented in this Dr. Sean Kane 20:25 trial, given that there were a lot of big exclusions for sprint, that's saying a lot, Speaker 1 20:31 right, right? So like anytime you sit down with a patient, you look at how he's doing, you look at safety and efficacy parameters. So again, we see side effects of the medication, we can chat with him. Is he experiencing orthostasis? Is he experiencing dizziness? We may even consider getting an electrolyte panel as well to see, you know, are we concerned about hyponatremia, hypokalemia, for example. And based upon this, though, we can consider increasing the Lisinopril dose. We technically could consider adding a second medication. But there's also the the idea about finances, and something we always have to remember is adding a second medication equals another copay versus increasing the dose of the medication. We can, we can avoid that again, some places like our facility, you know, it's the same price, one dose versus the other, and so the individual may not see a change in price there, which we can use to our advantage. Dr. Sean Kane 21:21 And you know, if you were going to add another blood pressure medicine, although I'm not a fan of hydrochlorothiazide, especially if he's sensitive to his co‑pay, he could potentially get a lisinopril/hydrochlorothiazide combo, which is probably one of the reasons why hydrochlorothiazide is so popular — it comes as a combo. So if we were to increase his regimen, that is something that you could consider Speaker 1 21:41 as well. And then again, just back to this, you know, quote, sprint fashion, but consider rechecking the blood pressure to see is it act how much lower it is. Perhaps that change of nothing other than time may, in and of itself, do some good. And so I'll just remember to or that we need to take an accounting for that as well. Dr. Sean Kane 21:58 And I don't know how you two feel, but even like home blood pressure monitoring, if they have a reliable cuff that does remove the issue of white coat syndrome, and if you see his blood pressures at home are truly 120s then when he comes to your clinic, it's 140s that's a pretty clear cut case that either he's got a bad blood pressure cuff, you have a bad blood pressure cuff, or he does truly have a white coat syndrome, and it's not representative of what his blood pressure is like when he's walking around. Dr. Khyati Patel 22:25 And I've done that to some of my patients who I perceive to have a white coat hypertension. That, you know, I make sure that I they have a good blood pressure and monitor at home, that they follow good procedures to check their blood pressure at home, and then bring me the values, and I can look at the trend that way. Speaker 1 22:41 Same here, same here, both patients and family members alike, yeah. Dr. Khyati Patel 22:45 And I think either approach is good. I mean, the starting medications this trial considered were either a thiazide type diuretic or an ARB, and he's already on an ACE, so we can either increase the dose or add, like Dr. Kane said, hydrochlorothiazide over here. But the main point from this trial is that that little benefit we're seeing is just one, one year of therapy. And so the ideal thing is, since he's 55 and hoping that, you know, he doesn't have a whole lot of morbidities or comorbidities and other medications, he does have good years ahead of him. So the idea over here is to maintain that blood pressure control over the years of time, and not just for that one year. Dr. Sean Kane 23:26 So let's summarize some of the key points from the SPRINT trial. For me, who is included, you know, this is a very specific patient population. We're looking at older, non diabetic patients who have some risk factors for cardiovascular disease. And in the SPRINT trial, they randomize them to roughly around 120 systolic versus less than 140 systolic. Speaker 1 23:44 So another thing we can look at is that patients were randomized to the lower blood pressure goal of intensive therapy. So those individuals did experience a reduction in cardiovascular outcomes. And although it was not anything specific, such as stroke, there was an overall benefit in all cause mortality. Dr. Khyati Patel 24:00 And patients in the intensive control group needed more number of medication, which resulted in some of the side effects, such as renal impairment, lowering of the blood pressure, hypotension and some electrolyte abnormalities, were seen as well. Dr. Sean Kane 24:14 And really in the aftermath of this one year that we've had a chance to look more closely at the SPRINT trial and its methodology. One of the big things to come out of it was how they checked the blood pressures and how it has poor external validity to how we actually check blood pressures in most clinics. So really emphasizes that maybe a sprint blood pressure of 120 is more like a 125 or 130 we don't know, and that's one of the problems, and it's unlikely that this trial will be repeated again, but it does offer us the suggestion of rechecking blood pressures home, blood pressure monitoring, trying to avoid some of the white coat syndrome that can happen in a clinic setting. Speaker 1 24:52 And I think it also the idea about not being so worried about these hard and fast numbers, and overall, getting a picture of the patient. The picture. Of their pill burden, a picture of their side effects, concerns on the medication and other factors that may contribute to higher blood pressure. Dr. Sean Kane 25:07 So with that, I think that kind of summarizes the SPRINT trial. Mr. Wilson fairly well. If you'd like to you can visit us online at HelixTalk.com we're also on Twitter at HelixTalk. We love five star reviews on iTunes to help other people find the podcast. With that. I'm Dr Unknown Speaker 25:21 King, I'm Dr. Schuman, and Dr. Khyati Patel 25:23 I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 25:26 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 25:37 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.