Combating A Silent Killer: An Evidence-Based Update on the Treatment of Hypertension

Hello, my name is Joseph Saseen. I am a professor and vice chair of the Department of Clinical Pharmacy and professor of family Medicine at the University of Colorado Anschutz Medical Campus. This presentation is called Combating a Silent Killer: An evidence-based update on the treatment of hypertension. I have no disclosures. What I would like to achieve over this lecture is first to explain some of the recommendations that we have from our standard of care 2017 American College of Cardiology, in collaboration with the American Heart Association Guideline for the Treatment of hypertension. Also, I plan on describing the evidence supporting bedtime dosing of antihypertensive medications. And lastly, I think with this information and other knowledge that I'll discuss throughout this presentation, that you should be able to formulate a care plan for a patient with resistant hypertension, not just based on the 2017 guidelines, but also based off of the 2018 American Heart Association's scientific statement of treatment of resistant hypertension. I'd like to start off with a quick polling question. The question I have for you is, which of the following describes the changes in hypertension control in the United States over the past 5 years? Is it A) increasing B) decreasing or C) consistently the same? Now, you may be surprised, but the correct answer, unfortunately, is D decreasing. Why do I say that? It's based off of data that we have from the NHANES surveys, and this particular analysis was published in JAMA in 2020. It's an analysis of data from 1999 to 2018, which evaluated over 18,000 patients with hypertension based on the National Health and Nutrition examination surveys or the NHANES database. And they defined control of hypertension liberally as less than 140 over 90, though a newer guidelines use lower thresholds. And we can see across the years, if we look at age adjusted proportion of patients with that controlled blood pressure, using less. 140 over 90 we see that it actually started to go up from 99 to 2000. It peaked actually at about 2013, 2014. But we see a very sharp decline amongst patients who were adults who are taking in hypertension medications, but also seen in all adults, even those who are not taking any hypertensive medications. So this highlights that we have a problem in treating, in particular to control blood pressure in our patients with hypertension in the United States. Some of this may have been influenced by mixed messages from things called the JNC8, which suggested a higher blood pressure goal of perhaps going to a goal of higher than 140 over 90 to 150 over 90. And we see that clearly that impacts the population. As far as those who were treated to a goal of less than 140 over 90. Unfortunately, this does have consequence. And the most important message I have for you is lower blood pressure is important because when we start to loosen up the blood pressure and go to higher blood pressure goals, we simply harm patients. These data were published in JACC, the American College of, um, American, Journal of the the American College of Cardiology in 2020. In this plot, hypertension related mortality and it shows in correspondence with the loss of blood pressure, goal that we have increased mortality both in the rural and urban populations in the United States. And it's not isolated to one region of the United States, even though it may have the highest impact in the south. We see even across the Northeast, Midwest and West, that there's an increase in hypertension related mortality. And I believe it's simply because we're not treating people as aggressively. Let's dive into the 2017 guidelines and understand why it's atrocious that this is happening. Well, first off, when we look at the 2017 ACC/AHA guidelines, they use the standard scoring scheme for evidence that ACC/AHA always uses in their evidence based guidelines. They make recommendations for clinicians on how to treat this condition. They apply a classification of that recommendation, which really imparts how strong or the strength of that recommendation or how much benefit outweighs risk. We have class 1 recommendations which are strong and will be labeled in green. We have moderate recommendations for class 2A, where benefit does outweigh risk, but maybe not as strong as a class 1. And then we have weaker recommendations which are 2B they still have benefit outweighing risk so that the ratio it's a little bit closer call there. Then we have some harmful recommendations, things not to do with your class 3 recommendations. So these class of recommendations are also coupled with the level of evidence, which is either A, B or C. Simply stated, A is based off of the best evidence, B is based off of moderate evidence, and C is based off limited evidence, sometimes purely expert opinion. So as a clinician, you can see when a recommendation is given, you can apply the classification, which is the strength of that recommendation and also the source of it, which is the level of evidence. The first thing that the 2017 guidelines did was redefine the threshold for hypertension. We can see that the categorization of blood pressure is based off of systolic and diastolic values, and the worst category prevails. But normal is considered a systolic blood pressure, less than 120 and a diastolic less than 80. Both of those have to be present to have a patient labeled as normal blood pressure. We see that elevated blood pressure are patients who have systolic in the 120s, but their diastolic is okay. It's less than 80 considered normal from a diastolic perspective that systolic in the 120s pushes them to the elevated range. These people are at risk for developing hypertension because once patients are in the 130s for systolic or above, they're considered either stage 1 or stage 2 hypertension. Those patients who have systolic in the one thirties with diastolic in the 80s are considered stage 1 hypertension, and those with systolics of 140 or greater or diastolics of 90 or greater are categorized as stage 2 Hypertension. This was a change from previous categorizations where it actually went down. What used to be 140 over 90 now it's 130 over 80 to define this clinical condition. This corresponds to about 46% to 48% of Americans who are adults meeting this categorization of being hypertensive. The goal blood pressure for most patients based on evidence is less than 130 over 80, which is in the hypertension range. We see that for patients who are higher risk, meaning those with known cardiovascular disease, known diabetes, known chronic kidney disease, or just a ten year risk of ASCVD based on the pulled cohort equations of 10% or greater, that we have a very strong recommendation that their target goal blood pressure should be less than 130 over 80. That's a class 1 recommendation with B or C level of evidence, simply because some of the data that we have doesn't always achieve the same amount of blood pressure instruction each patient. I'll go a little bit further with that. For younger patients who are healthier patients, I should say, who don't have known cardiovascular disease, don't have diabetes, no CKD and have a 10 year risk score of less than 10%, we still have a goal of less with 130 over 80, but it's a lower evidence because we have less people from our evidence source that were in the healthy range. It's still recommended, it's a weak recommendation just based on evidence, but still less, 130 over 80 prevails. Even in older patients take a look at this one. We have a class 1 level of evidence A recommendation that older patients who are 65 or older living in an ambulatory setting, meaning they're not institutionalized, that most of these patients should be treated to a systolic blood pressure goal less than 130. In far older patients when the systolic is less than 130 almost always their diastolic is less than 80. So we focused mostly on systolic values in that population because of the nature of blood pressure. Or we have this isolated systolic hypertension phenomenon adult develops with advanced age. Now you may question what is the evidence behind that less than 130 over 80? Well, a big driver, not the only driver per big driver was the SPRINT trial. We've heard about the SPRINT trial. It was published in 2014 and it was actually published after 2014. But the study design in 2014 told us that it's NIH funded study, so not by industry but by the national government was a multicenter, randomized controlled trial on over 9000 patients with hypertension. And these patients had additional cardiovascular risk factors. But there were randomized to an intense treatment arm, which was a systolic blood pressure goal of less than 120 versus a standard treatment, which was a systolic blood pressure goal, less 140 with end point being evaluating whether there's a difference in heart cardiovascular events defined as the first occurrence of a myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death as the primary end point. I call that hard cardiovascular outcomes end point. We look at the study criteria carefully. Patients were required to be at least 50 years of age and have increased risk of ASCVD based on additional cardiovascular risk factors, known things like low HDL, smoking status, family history, those types of things. Patients that were excluded were those with known secondary causes of hypertension. And that makes a lot of sense. If there was a reversible cause to not include in the trial. Importantly, they did exclude patients with diabetes prior strokes because there were some data that that maybe these populations shouldn't be included in this trial. Also, patients with systematic or symptomatic heart failure within the past six months, and mostly the half ref profile with ejection fraction less than 35 were excluded, as were patients with severe chronic kidney disease defined as proteinuria of more than one gram per day. Polycystic kidney disease or glomerulonephritus. And also patients with GFR estimated GFR less than 20 mls per minute per 1.73 meters squared, implying that they were approaching end stage kidney disease. In the SPRINT trial, what was used was standard medications, ACE inhibitors, ARBs calcium channel blockers and thiazides as first line agents. They did reserve beta blockers for those with coronary disease. The thiazide that was preferred was cchlorthalidone based on literature in historic use, showing that it is a good thiazide diuretic to use in hypertension and the calcium channel blocker that was preferred for use was also amlodipine, which which does mirror what we see in clinical practice. Now, the titration was based off of three office based blood pressure values. And I say this because they really did an excellent job of evaluating somebody's true blood pressure, since we don't always do three blood pressure measurements in clinical practice when were titrating medicines they used an automated device. They had a special protocol where patients were in a dark room and they actually evaluated the three measurements in five minute wait increments, which is not always it's great to do in clinical practice, it's just not what we always see because the frequency of measurement and screening for hypertension really was quite rigorous. The results of the SPRINT trial were overwhelmingly positive. So let's look at the instance of the primary endpoint throughout time. The study was actually stopped early after 3.26 years median time there because there was a clear separation with intensive treatment versus standard treatment, where intensive treatment was associated with a 25% relative risk reduction in the primary endpoint that was statistically significant and corresponded to a number needed to treat approximately 60. So because it was a hard cardiovascular end point this was considered highly statistically significant and clinically significant too. Another thing that's important as there's been some follow up studies showing that not only was there decreased incidence of a cardiovascular event, but they did a follow up study that to estimate prolonged survival, and it was estimated that the extension of life and patients randomized to intensive treatment was anywhere between six months and three years. And keep in mind, this was only in a study that was stopped after 3.26 years. So it may have been bigger if the study went on and those curves continue to separate. So not only was there the heart cardiovascular endpoint reduction, there's also a good estimation that patients live longer. SPRINT trial was a very large trial and influenced the guideline recommendation to go to a target of less than 130 over 80. But wasn't the only bit of evidence. We also have a very robust network meta-analysis that was published before, right around the time of the guidelines, actually a little bit before the guidelines as some of the supporting evidence and the objective of this network meta-analysis was to assess the association between mean systolic blood pressures with cardiovascular and all cause mortality events. Really looking at the available trials pulling over 42 clinical trials that are published in the literature representing over 140,000 patients and looking at their achieved blood pressure values. And correlating that to the incidence of cardiovascular events because you can imagine when you randomize people to less than 140 or less than 120, that you have a big dispersion of where people fall. Some people are in the 120, some in the 130, some in the low 130, some of the high 130s. It's a study we looked at where patients of true average blood pressures were. And we can see the comparisons on this particular graph. This fours plot shows us that lower is better, that lower blood pressure values always were more favorable at having reduced cardiovascular events versus higher blood pressure values. We saw many different comparisons listed to the left. And just for example, if you look at the ones in the red boxes, this compares patients with systolic blood pressures in the low 120s versus in the 130s, actually low end of 130 and the higher end of 130. In all of these comparisons where the referent was in the low 20s versus higher values showed that the lower blood pressure, lower achieved blood pressure was better than the higher achieved blood pressure values. And in my perspective is if you're targeting less than 130, you hope that patients land in the 120s. We can see that in those comparisons. When you compare that the people who landed in higher blood pressure range, that ranges the low 120s was superior for cardiovascular event lowering, justifying the less than 130 systolic goal. And when less than 130 is achieved, we almost always have a diastolic value that also is less than less than 80, especially in our older patients. Now, you may be thinking the patients that are most at risk for lowering blood pressure too much and causing side effects are older population. So I do want to focus a bit on the SPRINT seniors substudy of the SPRINT trial. This was a preplanned part of the SPRINT trial. It was specifically funded by NIH to look at patients 75 and older. Patients were randomized based on whether they were 75 and older. So this study was actually a substudy that had the power to see differences. The exclusion criteria for the 70 plus year olds in the SPRINT seniors component of SPRINT were patients with the diagnosis of dementia, or if their expected survival was less than three years because of a terminal diagnosis. Unintentional weight loss, hypotension when standing, so that orthostatic phenomenon, or those who lived in a nursing home meaning that they weren't ambulatory. Now this SPRINT senior substudy went a little bit more than 3 years. And the results were overwhelming. We could see that on the right, the outcome results, if you look at the primary outcome of cardiovascular disease, that it was 34% lower with intense treatment versus standard treatment, actually a little bit better results than seen in the total population. And if you correlate that to a number needed treat, we see a very favorable number that is much more robust and lower than this than the 60 that was estimated in the total population. Even all cause mortality was lower, 5.5% with intense treatment versus 8.1% with standard treatment, which is a significant benefit in patients. Now, important thing to note is if we look to the left and we look at the chief blood pressure values overall, the total SPRINT seniors population, those randomized to less than 120 didn't really achieve it. The average systolic blood pressure was about 123 mean that some people weren't able to be treated to those lower blood pressure goals. They still got the 120s, but not less than 120 because of the dose limiting side effects. Even in the frail population, their average systolic blood pressure in the tens group was about 124. So the message here to me is that in our elderly patients, even though we may target less than 120, we have to accept that some of them are in the 120s because of tolerability issues. That really does justify that recommendation. You know, if we go back to what the ACC/AHA guidelines recommended, it was a systolic goal of less than 130 for patients who are older, 65 or greater, not institutionalized, meaning they weren't in a nursing home with with without a limited life expectancy. So it was more than three years. This the SPRINT senior study justifies this class 1 level A evidence recommendation. But I do want to recommend for you to really evaluate your patient. If you do have a patient who is 65 or older, who has a high burden of comorbidity, who's living in a nursing home, or who has a limited life expectancy, maybe they have dementia or they have some other terminal diagnosis, don't use the less than 130 goal. You may have to use a higher goal. Make a patient centered decision. Maybe that systolic blood pressure goal should be less than 150 or less than 140, but certainly don't pick the stringent less than 130 in that population, because that's a frailer population that was not included in the SPRINT trial that we may need to make a patient centered decision to raise the blood pressure goal. That would be the exception to the norm. Going a little deeper into the 2017 guidelines, there's a treatment algorithm for recommended treatment for patients after diagnosis. This algorithm is really not great for patients with established hypertension already on treatment. It's to establish what initial treatment should be. We said patients with normal blood pressure don't need to be treated with antihypertensive medications, just lifestyle modifications with careful analysis on a yearly basis to see whether they develop hypertension For those patients who are creeping close to hypertension, these people with elevated blood pressure. So their diastolic is good, but their systolics in the 120s are close to being diagnosed. We do recommend very strong lifestyle modifications and they should be checked every 3 to 6 months. Then we have the stage 1 and stage 2 hypertensive patients who present with initial diagnosis. Those patients in stage 1, if they have a 10 year risk score for ASCVD using the pool court equation so that's less than 10%, meaning not people with cardiovascular disease, typically not people with diabetes or CKD, but healthy primary prevention patients, their risk score is less than 10%. We recommend nonpharmacologic therapy even if they’re in stage 1, even if we have a goal of less than 130 over 80, we can accept that it might be slightly above their goal and not be on drug therapy. We try to treat them with lifestyle modifications and reassess every 3 to 6 months if that same stage 1 patient does have a ten year risk score of 10% or greater, or if they have diabetes, chronic kidney disease, we would go with lifestyle modifications plus medication monotherapy as their initial treatment choice and follow up after one month. How does that compare to our stage 2 population with initial presentation of hypertension? Well, initial therapy should be nonpharmacologic with antihypertensive medication. Matter of fact, some of those people might require two medicines if they have a really far from goal blood pressure values and also to reassess at one month. Now we think of lifestyle modifications. Not a whole bunch has changed here. All these nonpharmacologic interventions are class 1 level of evidence recommendations, proven entities. So weight loss in patients who are overweight or obese does lower blood pressure, and the more weight reduction, the more blood pressure lowering. Recommending a DASH eating plan, which is a heart healthy diet that's high in fruits and vegetables and high and low fat dairy products does facilitate blood pressure lowering. Sodium restriction, ideally to less of 1.5 grams of sodium per day but at least cutting it down by 500 to 1000 milligrams per day is a recommendation that lowers blood pressure. And most people potassium supplementation through the diet, through mostly increasing fruits and vegetables unless contraindicated should be recommended. Increasing physical activity using a structured exercise program, really trying to target 150 minutes of accumulated moderate intensity physical activity per week is recommended, and also alcohol restriction. No more than two drink equivalents per day for men or one drink equivalent per day for a woman. Recommendations for medication selection. We have all Class 1 recommendations here and some strong recommendations which are considered level of evidence A based on the systematic review that the guideline group did themselves indicates that first line therapy does still exist within using thiazides, calcium channel blockers, ACE inhibitors, or ARBs. Those are our top four drugs for most patients with hypertension because of evidence that they reduce cardiovascular events better than placebo and also better than some other antihypertensive options. So these are top four for most people. There are some exceptions to that I will go over too. We also have our strong recommendation with Class 1 with based on expert opinion that patients who are far from goal, meaning if they need more than 20 over ten millimeters of mercury reduction to more than 20 systolic reduction or more than 10 diastolic reduction that we should start with two antihypertensive medications. And this has been around since 2003, that recommendation with the JNC7. What people are far from goal. But I think we really need to appreciate it because most people do need two drugs to control their blood pressure. We see that recommendation in the last one there. We also see for black patients that perhaps instead of just picking from our list of four, that initial treatment should be comprised of either a thiazide or a calcium channel blocker. And this assumes that there's no heart failure or chronic kidney disease. But if you have a black patient without heart failure, chronic kidney disease, a thiazide or calcium channel blocker, we'll get better blood pressure reduction than an ACE inhibitor or an ARB. And that's when you have the affordability in stage 1hypertension of just using monotherapy. That should be a consideration. Now, here are some exceptions to the rules where we don't just pick thiazide, calcium channel blocker or ACE inhibitor or an ARB. When we have a compelling indication for a specific drug class, we should rethink that process. Here are six classic compelling indications and there may be a few other ones that are less common. But heart failure, whether it's reduced ejection fraction or preserved ejection fraction, stable ischemic heart disease, diabetes, chronic kidney disease and secondary stroke prevention may be some exceptions to the rules. In particular, we look at HFrEF, heart failure with reduced ejection fraction or stable ischemic heart disease or even HFpEF that matter, which is preserved ejection fraction. We see that beta blockers are part of the first line pharmacotherapy regimen that's recommended, that's proven to reduce events, and that's because beta blockers under these contexts have extra special benefits at reducing cardiovascular events. They often have to be used in combination with an ACE inhibitor or an ARB. Both of these treatment options, all these treatment options in the first line will both lower blood pressure and also reduce cardiovascular events, particularly in this compelling indication. There are some proven recommendations for some of these thereafter as add-on therapies, but I think you may get the gist that this is these are situations where we think twice. Diabetes is the one where we still can use any of the four top four drugs ACE inhibitor, ARB, calcium channel blocker or thiazide. It used to be that previous guidelines recommended in diabetes to go preferentially with an ACE inhibitor or an ARB, but it seems as though there's not that much of a difference between those options unless there is the presence of chronic kidney disease indicated by a decreased GFR or persistent albuminuria where we should go with an ACE inhibitor or an ARB with because of those special effects of preserving kidney function longer. There's also Class 1 recommendations about follow up after initiating drug therapy. It is extremely important, not just to look at blood pressure response, but also to evaluate adherence to therapy to assure that patients not only have good looking blood pressures that are on target, but also that they're adherent with their anti-hypertensive regimen, whether that is drug therapy with lifestyle modification or lifestyle modification alone. There's also a very strong recommendation, Class 1 level of evidence to have follow up monitoring using strategic and systematic strategies which use home blood pressure monitoring and team based care and even telehealth strategies to actually assure that we get patients to goal, and we keep them that goal. Those are proven strategies to do that. Matter of fact, thinking of home blood pressure monitoring, there's been a lot of momentum in this area. The American Heart Association has a policy statement about self measurement of blood pressure. It’s strongly encouraged. It's indicated to identify white coat hypertension or masked uncontrolled hypertension. But if you think about the evidence for patients with chronic hypertension, self measuring the blood pressure is associated with both reductions in blood pressure and improved blood pressure control and also better cardiovascular outcomes. There's an association between that. It's all also considered cost effective as a way to maybe and during times of pandemics, it's great to actually treat patients based on their home blood pressure measurements because you may not have to bring them into clinic and expose them to other things. But there is a lot of value that's cost effective to treat and titrate therapy based on how measurements versus exclusively doing it based on office based measurements. With antihypertensive drug therapy, we need to be diligent, especially when we're treating to blood pressure goals of less than 130 over 80, which should reduce cardiovascular events more. And if we do that, we maybe can reverse some of the increase in mortality related to hypertension that we're seeing. But when we treat patients to those more aggressive blood pressure goals, I'm comfortable with that. But we need to do drug therapy monitoring, not just looking at blood pressure, but we need to look at other adverse effects that may be present with our drug therapy since we're reliant on drug therapies. One thing to keep in mind is in the SPRINT trial, when they were targeting systolic blood pressure goals less than 120 and achieved about 120, they typically need about three antihypertensive drugs. So you may expect that that's needed in a lot of patients. We need to do our drug therapy monitoring for adverse effects. All of them are summarized here. A simple one. One to just highlight with ACE inhibitors and ARBs are usually very well-tolerated therapies. But when you did look at kidney function because sometimes we may see a bump in serum creatinine and usually an increase in serum creatinine of up to 30% is safe. But if we have a doubling of serum creatinine, we may have unmasked a patient with bilateral renal artery diagnosis that may indicate stopping the ACE inhibitor or the ARB. Thank goodness it only happens rarely in less than 1% of patients. But it's one thing a small bump is acceptable, but more than 30% is when we need to think twice. And also keep an eye on serum potassium for that one. We know that there's electrolytes that need to be monitored for diuretics, mineralocorticoid receptor antagonists, and it's a little bit more strict for beta blockers and calcium channel blockers where we need to keep an eye on heart rate. I do want to talk a little bit about the side effects that we see with calcium channel blockers. Calcium channel blockers are first line therapies and dihydropyridines like amlodipine are really are most common calcium channel blocker that we use to treat hypertension. Calcium channel blockers do a great job of lowering blood pressure, especially dihydropyridines like amlodipine. We do note that there's an increased risk of peripheral edema because of the strong arterial vasodilation that we see with amlodipine and other dihydropyridines and it is clinically significant to keep our eye on. It's a dose dependent phenomenon, but there's some data from different cohort studies. The one on the left is a cohort study in over a million patients who were younger, less than age 65, who started a dihydropyridine calcium channel blocker. And what was noted in this trial was there was an excess prescribing of loop diuretics in lieu of just reducing the dose of a calcium channel blocker. And the reason why I think that's important to note is that it's commonly seen, but it's not good to do. Diuretics will not relieve peripheral edema from calcium channel blockers. They just don't. The reason that people get peripheral edema from a calcium channel blockers because you're providing strong arterial vasodilation but not veinous vasodilation, so you have an imbalance across your capillaries in your periphery where there's you know, lowering of blood pressure on arterial side, but not the veinous side and it causes spilling through the capillaries and the manifestation of peripheral edema. The best way to deal with that is to reduce the dose of the dihydropyridine calcium channel blocker or co prescribe in ACE inhibitor or an ARB to neutralize some of that pressure balance. But don't use a diuretic, especially a loop diuretic, because it's not going to pull the fluid off of just your pedal area. This is also seen in older patients. It's a cohort study looking over 40,000 patients. Age above 65, mean age of almost 75 years of age. You start a calcium channel blocker thing and same thing. A twofold increased prevalence of starting a loop diuretics thereafter. And this was persistent over a period of year of years. So I guess the message I see here is predict that some patients may have peripheral edema with a dihydropyridine calcium channel blocker and think, you know, if you can't alleviate that with lifestyle modifications, reduce the dose or co prescribe an ACE inhibitor an ARB if the blood pressure can tolerate it, as two better strategies to manage pedal edema or peripheral edema versus using a loop diuretic, which causes a slew of other problems. I'd like to pose another question for you, and this is a little scenario. I want to assume that a patient's treated with one antihypertensive drug at the normal starting dose. And after four weeks, they're still not at their blood pressure goal. My question is which of the following strategies is most likely to lower blood pressure the most? Would it be a) waiting another four weeks? b) adding a second antihypertensive drug? c) doubling the dose of the antihypertensive drug? or d) replace the antihypertensive drug with another one? And this might not be what you do in practice, but if I really, you know, held you accountable to which these options could lower blood pressure the most, it's not a) just waiting another four weeks. Four weeks is sufficient to get your time. But really the answer would be b) adding a second drug. Why do I say that? It's based off of data. This is a wonderful analysis is published over ten years ago, but the results are still true and it looked at the incremental change in systolic blood pressure that was observed with major drugs like thiazides, beta blockers, ACE inhibitors, calcium channel blockers, and then all antihypertensives collectively. Well, in the in the left bar, the blue bar represents the systolic blood pressure reduction by adding another drug class versus the lighter blue bar in the right shows the systolic blood pressure reduction by doubling the dose and clearly adding another drug class because of complementary actions on how to lower blood pressure was more effective. Matter of fact, if you look at all the classes together because it's pretty consistent, whether you're looking at thiazides, beta blockers, ACE inhibitors or calcium channel blockers look at them all together. It was about a five times more effectiveness of lowering systolic blood pressure when you added another drug versus just increasing the dose. Now, I realize there are many times where you may increase dose prudently and we may do that, especially with ACE inhibitors or ARBs in patients with established heart disease or kidney disease to really capitalize on the blunting of the angiotensin two effects to minimize kidney progression or cardiovascular disease progression. But if you're looking purely at just blood pressure lowering or better off using combination therapy to achieve blood pressure lowering than we are to just maxing out the dose of an individual drug, we increase the dose, usually increased side effects, but using lower doses together are the most complimentary way to maximally reduce blood pressure. I do want to talk a bit about bedtime dosing in hypertensive medicines. This is something that's been on and off over the past 20 years or so and bedtime dosing and hypotensive medications really is designed to target the normal diurnal pattern of blood pressure. We know that blood pressure dips down as we go to sleep and it starts to rise at about 3 to 4 in the morning when we're still asleep. And, you know, when we wake up about 6 a.m., it's still on the rise and it peaks at about, you know, up to noon time. And then it goes down throughout the day and then we fall asleep. And this continues to go down so it’s that diurnal rhythm. The concept of bedtime dosing is give your antihypertensives at bedtime, so that when they start really kicking in, it can blunt some of the surge in blood pressure. And some studies have found that evening dosing of cardiovascular drugs may be associated with less cardiovascular events. The HOPE trial gave ramipril at bedtime, even though not all those people were hypertensive. It had favorable results versus placebo. And that sort of started some of this. There's been some other studies that actually looked at cronotherapeutic drugs which have delayed onset that it really did show a benefit. But we have seen a resurgence because there's been some studies looking at bedtime dosing. One of them in particular is called the Hygia Chronotherapy trial. This was a pretty large, multicenter, randomized trial out of Spain, where over 19,000 patients with hypertension were randomized to bedtime dosing of at least one of their antihypertensive medicines versus giving all of them in the morning. Now, as far as internal consistency, there wasn't really standard regimen of which drugs to use at that time. Patients were given the guidance of take at least one of your medicines at bedtime, maybe all of them, maybe half of them, maybe just, but at least one of them with no real preference of which one would do. They also required in this Hygia Chronotherapy trial that patients had a 48 hour ambulatory blood pressure measurements for inclusion and monitoring of ongoing therapy. The primary outcome was a cardiovascular event, MI, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke and cardiovascular death. So a hard cardiovascular endpoint. Now this Hygia trial showed overwhelming benefit of dosing at least one of your antihypertensive medicines at bedtime. If you look at events, there were just 43% total cardiovascular events. Everything was good. I mean, these were huge differences, more than what we've seen in any other trial in this study from Spain, where patients were said were told to take at least one of your antihypertensives at bedtime. Maybe all of them, maybe one of them, maybe two of them. But at least one of them versus regular morning dosing. These results got a lot of attention because they were overwhelmingly positive. Matter of fact, they were too good to believe probably. What many people know about these Hygia results, and they just know that the message, oh, it might be good to take your medications at bedtime if you have hypertension or at least one of them. But what they may not know is that these results are probably too good to be true. They're actually under investigation. The journal that published it, the European Society of Cardiology Journal, which is a European Heart journal, a very respected journal, actually has a write up that these results are under investigation and we suspect that they were falsified. What the Journal editors decided to say in this publication was the content and conduct of this randomized controlled trial is currently under investigation, and they tempered any interpretations. They recommended that that clinicians don't interpret these results until there's further adjudication. So anything you hear about bedtime dosing of an antihypertensives based on the Hygia trial simply expunge from your memory, since it may be too good to be true. I don't recommend it based on the scrutiny and investigation of this trial. I would like to talk a bit about resistant hypertension. Resistant hypertension is defined as patients with hypertension, where you've ruled out secondary causes who require if you look at the definition for the 2018 scientific statement, concurrent use of three antihypertensive medications commonly including a long acting calcium channel blocker, an ACE inhibitor or an ARB and a diuretic, all three of those at maximally tolerated daily doses. So three of the medicines all at good doses, yet not at blood pressure goal. That's one definition of resistant hypertension. An alternative definition are patients who are on four antihypertensive drugs, regardless of whether they are at their blood pressure goal, um, just implying that these are resistant hypertensive patients where there may be another driver increasing their blood pressure. Now with resistant hypertension, it's very important to rule out secondary causes, whether they are medication causes, other causes or diseases which may be responsible for the refractory high blood pressure. Just to comment on a few episodic use of NSAIDs or even chronic use of oral contraceptives that contain estrogen can raise blood pressure and they’re common secondary causes when you have a drug induced cause. We often sometimes see some other things like steroids. Cyclosporine is sometimes is also a culprit. Excessive alcohol use or cocaine use. Some diseases, mostly kidney diseases, but also things like obstructive sleep apnea can raise blood pressure, be a secondary cause. So all of these should be ideally ruled out before we label somebody as having resistive hypertension. That's what's called for in that 2018 scientific statement. A question I have for you, though, on the theme of resistant hypertension is, Which of the following is a common cause of pseudoresistant hypertension? What is pseudo resistant hypertension? Well, looks like resistant hypertension, but it's not. So what's what's the most common cause of people looking like resistant hypertension but they really don't have it? Is it a) inaccurate blood pressure measurement? b) white coat hypertension? c) undertreatment? or d) medication non-adherence? And when I think about this one, I, I would have guessed wrong. If I didn't know the data, I probably would have guessed non-adherence or I may have guessed inaccurate blood pressure measurement. Now those are common causes of pseudo resistant hypertension, but the most common one here is Undertreatment, not maximizing our drugs. The AHA scientific statement shows us this data. They're all important to rule out as pseudo is things that are clouding the picture, making it look like it's resistant hypertension. But it's not. But Undertreatment is responsible for about 70% of the time for people who look like they're resistant hypertension when they're not simply their doses have not been maximized. That's simple as that. Inaccurate blood pressure measurement is discernible. It's important, as is white coat or non-adherence is important drivers of people looking like they're uncontrolled resistant hypertension when they're actually not. So what's recommended by the AHA scientific statement, they have six different steps to treating resistant hypertension, and the first three are evidence based. So excluding other causes, ensuring lifestyle modifications, especially a low sodium diet and optimizing that three drug regimen is important. It’s basically needed to establish whether you have resistant hypertension or not. And once you have established it with step 1 the first drug therapy option is swapping out hydrochlorothiazide for chlorthalidone. So switching a less effective thiazide with a more effective thiazide. And we can talk about that a little further as a proven beneficial step 2 recommendation. step 3 after that would be considering the addition of a mineralocorticoid receptor antagonists like spironolactone or eplerenone, assuming that there is preserved kidney function and not risk for hyperkalemia, those are the most effective treatments for resistant hypertension. There are step 4, five and six, which are recommendations to add a beta blocker or even an alpha blocker or a central acting alpha agonist in some patients at step 4, not based on evidence looking at resistant hypertension, there may be compelling indications where you go with a beta blocker, but this isn't considering that this is just your run of the mill resistant hypertensive patient. After that, maybe use hydralazine or minoxidil depending on the patient. And if that doesn't work, considering referral to a specialist. These are the recommendations and hopefully we can manage many patients with step 2 and step 3. If we dive a little deeper into step 2, that was changing hydrochlorothiazide to chlorthalidone. What's the deal between these two thiazides? Hydrochlorothiazide is a pure thiazide type diuretic where chlorthalidone is thiazide like, doesn't include thiazide in the name. Think of it that way. There's a much longer half life with chlorthalidone of up to 60 hours versus about 9 to 10 hours with hydrochlorothiazide. So that actually will impart maybe a better long term blood pressure lowering profile. If you look at the equivalent doses, basically about 25 milligrams of hydrochlorthiazide is about equal to 12 and a half of chlorthalidone, maybe a little bit higher. So it's about a 2 to 1 ratio as far as looking at blood pressure, potency. And we also know that even though hydrochlorothiazide is very frequently used in combination products, chlorthalidone is the one that's been used in long term outcomes trials. One thing I do want to say, even though there's a very strong recommendation for step 2 that chlorthalidone is stronger than hydrochlorothiazide and it is, there is some question about the long term benefits of the differences. There's a cohort trial in over 700,000 patients who are prescribed hydrochlorothiazide and chlorthalidone that was published in 2020. It didn't show any differences. It was a retrospective cohort. So that is somewhat limiting. But didn't show a difference in hard cardiovascular endpoints. The hazard ratio was equal amongst both groups. And chlorthalidone was, because it's stronger, associated with more metabolic like side effects such as hyperkalemia and hyponatremia versus hydrochlorothiazide, probably just because it was stronger. But it is clear that there's more blood pressure lowering with chlorthalidone, we're just a little bit unclear whether that correlates to a difference in cardiovascular events based on your data. We also have that step 3 recommendation, which is adding a mineralocorticoid receptor antagonist, and there's lots of data to support this. One in particular is the PATHWAY-2 trial. This was a double blind randomized crossover trial, so it has a lot of value there in over 300 patients who had resistant hypertension. And they were treated for three months, which is 12 weeks with either Spironolactone, Doxazosin, Bisoprolol or placebo. And we can see if we look at just systolic blood pressure reduction from baseline, which was the primary endpoint that spironolactone was superior compared to the other options. One thing to note though, when we do use Spironolactone, which is the mineralocorticoid receptor antagonist, that there is a risk for hyperkalemia which must be monitored for. Some patients can have significant elevations that absolutely requires diligent monitoring. Other things that are included in the AHA statement on resistant hypertension is our recommendations in step 4 beyond to use an alpha blocker, a central acting alpha agonists or an arterial vasodilator. What I do want to say about these agents, they are considered alternative antihypertensive agents. I have a better comfort level with beta blockers than I do with these. And it's really because there's usually excess side effects and not that long term proven benefit of cardiovascular risk reduction. Some of the side effects are summarized here. But there is one thing I want to call in particular. The AHA scientific statement talks about the use of one particular central acting alpha agonist, which is clonidine. clonidine we see frequently used in clinical practice, but clonidine can cause rebound hypertension and clonidine can also cause anticholinergic side effects, which can be limiting, especially in our elderly patients. While matter of fact, this is the first strong statement I've seen against using clonidine. The strongest one I've seen. It says that clonidine tablets should be avoided in resistant hypertension because a need for frequent administration and the risk of rebound hypertension when you have non-adherence or when you stop the drug. If clonidine is to be used, they recommend actually using the transdermal product, which we don't use a lot in clinical practice. And I still see a lot of clonidine use and I always sort of cringe a little bit because of the side effect profile, the rebound hypertension, but now I can say that the American Heart Association also cringes too. So I try to avoid it in our practice and I try to get people off clonidine even though I know it does lower blood pressure. There's just too much risk associated with it related to side effects and rebound hypertension. One last thing I do want to keep in mind is the concept of adherence. I love this quote from C. Everett Koop, one of our former surgeon generals, somewhat the more famous ones. And he stated that “Drugs don't work in patients who don't take them”, which really says a lot to me. If we know that there's benefits of using certain antihypertensive agents in certain co-morbidities, we know that there's benefit of antihypertensive treatment to goal blood pressure values, that the benefits are prolonged life and less cardiovascular events. All that's great to know. But if our patients aren't adherent consistently with our antihypertension regimens, then they don't get those benefits. So this is a huge challenge or a barrier to imparting the best patient care for your patient with hypertension or persistent hypertension. Now, there's a lot of things that we can do to actually improve adherence, such as optimizing our drug regimens using cost effective or affordable treatment options, having open discussions with patients about tolerability, giving them the truth of why they should be treated for their hypertension that benefits they particularly will have. And we should use those. And always keep in mind, matter of fact, if you're not looking for adherence, you're not going to detect non-adherence anyway. So you need to be very cognizant of that in your monitoring. But I think we also need to be abreast of certain predictors of poor adherence amongst our patient populations. And these are ones that have been proven in the literature. One is patient care that has low patient centeredness is associated with poor adherence. What does that mean? It means if actually have more of a hierarchical relationship with your medical provider, with a patient, and you don't engage your patient, have that patient centered care where there's shared decision making and where they're weighing into their treatment options. That's if you don't have that, that's low patient centeredness and it is associated with a downside of people don't take their medicines, because they're not involved with the decisions. Another thing is when there's less discussion about sociodemographic circumstances, when you don't bring up in your clinical encounters or ask about living situations or relationship status, that there's that there's a higher risk of poor adherence. Matter of facet there’s even more of a negative influence of this among our black black patients, which have a higher risk of not only cardiovascular morbidity mortality from hypertension, but also sometimes have higher risk of resistant hypertension are more difficult to treat hypertension. So very important for them, and for all of our patients. Let's just face it. There's also encounters that have less discussion about specific medication issues also are associated with less adherence. And it makes sense when you don't focus in on explaining those. Maybe this is a call for using team based approaches. One clinician cannot always do everything, so really partnering with your pharmacist so that they can focus in on the nuances of drug therapy to give patients appropriate information, to encourage them to be adherent for their good so that they live longer with fewer cardiovascular events. So in conclusion, some of the messages that I wanted to share with you are that the 2017 ACC/AHA hypertension guideline does recommend a blood pressure goal of less tha 130 over 80 for most patients, and it's based off of evidence, not just one study but collectively from meta-analysis. And we also still have ACE inhibitors, ARBs, calcium channel blockers and thiazides as proven first line agents for most people. The exception to that would be the presence of compelling indications, where we go beyond that, perhaps. Evidence does support does not support bedtime dosing of antihypertensive medicines. It's unproven. So whatever people may think, remember that the Hygia trial is under investigation and it should not be followed because it's probably falsified. And lastly, I also think that it's important to remember that patients with resistant hypertension should be evaluated for post secondary cause and have them ruled out. And they require often multiple agents, multiple antihypertensive agents that are beyond first line therapies. We need to think about prudently using chlorthalidone when appropriate and also safely using a mineralocorticoid receptor antagonist when indicated.