 Good morning. I'd like to thank Stephanie Coulter for the invitation to speak with you today on the treatment risk paradox in blood pressure management. And I'm coming to you from New Hyde Park in New York on Long Island. I'm sorry I can't be with you in person but it's a pleasure to be speaking with you. So I'd like to start by talking about the current hypertension guidelines which came out in 2017. These guidelines created a lot of attention because they really changed our definition of hypertension as we defined it prior to 2017. And you can see here in this slide that prior to 2017, we defined normal blood pressure as 120 over 80. That hasn't changed since 2017. That is still the definition of normal blood pressure. And for individuals with normal blood pressure, we just encourage optimal lifestyle habits. Before 2017, starting with the 2014 guidelines, we defined blood pressures of 120 to 139 for systolic or 80 to 89 millimeters of mercury for diastolic as pre-hypertension, not unlike what we say with hemoglobin A1C when we define pre-diabetes. This was considered a warning, not true hypertension but a warning of the potential for developing hypertension. Then we had these two stages of hypertension, stage one for blood pressures 140 to 159 over 90 to 99, and stage two hypertension which was defined as blood pressures consistently above 160 or diastolics consistently above 180, above 100. So in 2017 these definitions got considerably stricter. So blood pressures between 120 to 129 were considered elevated blood pressure. And if systolic blood pressures ranged 130 to 139, or diastolic blood pressure ranged 80 to 89, this is now considered stage one hypertension. Blood pressures that in the past were considered normal. Stage two hypertension now is considered 140 for systolic or 90 or greater. In prior guidelines, this would have been the definition of hypertension. Now it's the definition of stage two hypertension. With elevated blood pressure or stage one hypertension, we recommend non pharmacologic interventions, and also considering therapy with blood pressure lowering medications. We certainly recommend antihypertensive treatment for stage two hypertension. However, when we're in these elevated or stage one hypertension range, we will often consider underlying conditions. So we might ask our patients if they have cardiovascular disease, diabetes, chronic kidney disease, or we may go to our ASCVD calculator and calculate a 10 year risk score. If the score comes out less than 10% or there are no concurring conditions, we may consider lifestyle modifications aiming possibly for a goal of less than 130 over 80. However, if any of these conditions exist, or there's a CVD risk greater than 10%, we will recommend treatment of blood pressure to a goal of less than 130 over 80. So how did we get to these newer stricter guidelines? Well, I've outlined here several studies that kind of paved the way to this. There are several studies that were done in elderly population. The SHEP trial, the Cysteur trial, and I might also add there was also a CysteChina study as well, and the Hyvet trial. We'll talk about the African-American study of kidney disease and hypertension, which looked at a population of individuals with high blood pressure and underlying kidney disease. And then two more recent trials, the Accord Action to Control Cardiovascular Risk Disease and Diabetes trial, and the Sprint Cystallic Blood Pressure Intervention trial. So let's first look at the studies in elderly populations. The SHEP trial, which was very well known by many people in the 1980s, recruited 4,736 patients, a large trial, they were at least 60 years of age. Blood pressure is ranging 160 to 219 millimeters of mercury for systolic. Diastolics were below 90 millimeters of mercury, so this was mostly a population of systolic hypertensive individuals. The active treated arm was treated to blood pressures averaging 143 over 68 versus the placebo group at 155 over 72. And the results of this trial showed a 36% reduction in stroke, 32% reduction in cardiovascular events, 27% reduction in non-fatal MI or coronary death, significant findings, and a 13% reduction in all-cause mortality, which is significant. Interestingly enough, in this study, they also found fewer adverse events in the treatment group compared to the placebo group. So adverse events was not so much an issue in treating blood pressure to a level of about 140 over 70 in this population. The SIST year, systolic hypertension in Europe trial, also a large trial, 4,695 patients at least 60 years of age, systolic blood pressures again ranging 160 to 219, diastolics below 95, randomized to treatment versus placebo, the treatment arm being focused on calcium channel blockers, the dihydropyridines, and the treated goal was to 151 over 80, the placebo averaged about 161 over 86. And given this difference in treatment, they also found significant reduction of events, 42% reduction in strokes, 26% reduction in cardiac events, 31% reduction in overall cardiovascular events. The last study in the elderly that I'm going to talk about is the HIVET study or hypertension in the very elderly trial. This study looked at 3,845 patients at least 80 years old, with systolic blood pressures that were at or above 160 millimeters of mercury, again randomized to treatment, in this case with pyrindipril and ACE inhibitor plus or minus endapamide, the diuretic versus placebo. And in this group, with a follow up period of up to five years, the treated group achieved blood pressures averaging 145 over 77 millimeters of mercury, and the placebo group 159 over 84 millimeters of mercury. And with this treatment difference, it was found that there was a 30% reduction in strokes, 39% reduction in stroke death, and a 64% reduction in the development of heart failure. Overall, a 21% reduction in all cause mortality and a 23% reduction in cardiovascular death. And again, in this study in the very elderly, it was found that there were fewer serious adverse events in the treatment group compared to the placebo group. So the conclusions from these trials seem to suggest that treatment to a goal of about 150 millimeters of mercury or less has benefit in terms of prevention of stroke, heart failure, cardiovascular events. So let's now look at the population with kidney disease. The African American study of kidney disease and hypertension looked at 1094 African American individuals. They were non diabetic hypertensives with chronic kidney disease baseline GFRs range between 20 to 65 milliliters per minute per 1.73 meters squared. The main composite outcome of this trial was the effect on kidney function, which included the time of declining GFR how much GFR changed over time or decreased over time. The development of end stage renal disease or progression to hemodialysis, and also death. And in this group, there were two blood pressure goals. There was a usual blood pressure goal and an aggressive or low blood pressure goal these were based on mean arterial pressure. So the usual goal was for a mean arterial pressure 102 to 107 millimeters of mercury, which is around the blood pressure of about 140 over 90. The more aggressive treatment goal treated to a mean arterial pressure of less than 93 millimeters of mercury or really treating down to 125 over 75 millimeters mercury on average. What's interesting in this trial to get to these goals, often required multiple agents, the agents that were used in this trial were dihydropyridine calcium channel blocker that's amlodipine, the endotensin converting enzyme inhibitor Ramapril and the beta blocker metoprolol. And you can see over the follow up time. Again, what's really striking for a trial such as this was that they were able to achieve their treatment goals and you can see that the aggressive treatment goal was achieved with an average of about 128 over 78 versus the usual treatment goal which averaged to about 141 over 85 millimeters of mercury. And what we see in terms of outcomes, overall events plotted on the y axis, a couple of interesting things. What appeared in kidney disease was that patients who were given the ACE inhibitor Ramapril did better than other groups. So you can see the Ramapril event curve, over here, fared better than either the metoprolol or amlodipine curves, which are rather close over here so no significant differences between Ramapril, between metoprolol and amlodipine, but significant improvement with the use of Ramapril. Another interesting finding in the ASC study was looking at patients based on the underlying presence of proteinuria. And in this plot here, we look at standard treatment, which is the dotted lines versus intensive control and plotting over time, looking at the cumulative presence of primary events in this study, the progression of decline of GFR progression to end stage renal disease and death. And we see that in patients who had significant proteinuria greater than 300 milligrams a day. There was a significant improvement in the intensive control group compared to the standard control group. This difference was present, but not at all to the same extent in patients that had no significant proteinuria, less than 300 milligrams per day. So that was an interesting finding. But again, in a highly risk group of hypertensives who have kidney disease, who have proteinuria, we see here that the aggressive therapy and use of ACE inhibitors had benefit, significant benefit. So let's move on to a trial that actually included diabetics. That's the Accord trial. And in this study, 10,251 subjects with high risk, hypertension, type 2 diabetes, stratified by intensive versus standard glycemic control were looked at. And in this study, there were 4,733 who were also randomly assigned to blood pressure control and intensive versus standard blood pressure control approach. And in this study, the intensive treatment goal was to less than 120 millimeters of mercury versus the standard treatment of less than 140 millimeters of mercury, with the outcomes being non fatal MI non fatal stroke and overall cardiovascular death. And then a very well done study in which over periods of time the intensive treatment goals were met very well, as were the standard goals. And again, just like with the ask study, you can see that it often took two to three medications to achieve blood pressure control. So one thing the ask study, the Accord and as you'll see in the sprint study showed us is that if you want to achieve strict blood pressure goal. You're going to need two to three anti hypertensive medications to get to that goal. The Accord study, when looking at primary outcome showed a 1.87% per year outcome in the intensive therapy group, which was really not significantly different than the event rate in the standard therapy group 2.09% per year with a hazard ratio of 0.88. This did not achieve any statistical significance. So it was quite a surprise that in the diabetic population. It did not demonstrated that intensive therapy led to significant improvement in primary outcomes. However, when they looked at predefined or pre specified secondary outcomes, which included any stroke or non fatal stroke. In those situations, they did see improvement in terms of lower stroke rates in the intensive therapy group versus the standard therapy group. And given these event rates, the number needed to treat to prevent one stroke over five years was about 92. So the Accord trial actually had some impact on our guidelines, particularly the ones that came out of Europe, as you'll see, and did not show findings that were subsequently shown in in the sprint trial which will get to the implications of the Accord trial are summarized here. The serious adverse events that were attributed to the antihypertensive treatment occurred in 77 out of 2362 participants in the intensive therapy group that's about 3.3%. And only 30 out of 2371 participants in the standard therapy group. So we did see more adverse events in the intensive therapy group. We saw that there were really about twice as many adverse events in the intensive therapy group. These were treatable treatable events metabolic hypotensive events they were not permanent they didn't result in death. So you have to balance that with the fact that there were half the number of strokes, which is usually a more permanent event. And that is something that is food for thought for those of us clinicians who are making decisions on how aggressive to treat our patients with hypertension. The failure of the Accord trial to show superiority in terms of the primary outcome led to the European guidelines to recommend more conservative goals for diabetic populations and we'll see that shortly. Let's now move on to the sprint, the systolic blood pressure intervention trial. In the sprint trial participants were high risk with more than with one or more of the following situations, clinical or subclinical cardiovascular disease, framing cardiovascular risk of 15% or more evidence of chronic kidney disease, older age, and in this case patients with a history of stroke or diabetes were excluded. So this is a unique kind of population so we often refer to them as the sprint population may not be extractable to all populations, but certainly a high risk hypertensive group. So this is an examining intensive treatment with a goal to less than 120 versus standard treatment to 140 millimeters of mercury in these patients similar to what was done with the Accord trial. And again, we see that over period of years that the ability to get the intensive treatment individuals to goal was quite good. Again, it required generally several antihypertensive medications, but they were able to achieve this goal as was achieved with the standard treatment group. And what was shown in terms of primary outcomes, the cumulative hazard ratios plotted here is that there was a 25% reduction in the composite primary outcome for those who got intensive treatment that primary outcome being cardiovascular mortality, non fatal MI stroke, and heart failure. So definitely a significant improvement with the intensive therapy group. What was also shown was that given that 20 cent, the 27% reduction in all cause mortality was that the number the number needed to treat to prevent one death was 90. The number needed to treat to prevent one primary cardiovascular outcome as defined by this trial was 61. So this does give impetus to being more aggressive in terms of achieving stricter blood pressure goals. There were fewer primary outcomes in intensively treated individuals ages 75 or greater. This group of individuals highlighted here, and these individuals experienced significantly fewer primary outcomes and significantly less all cause mortality when they were treated to a goal of 120. So again, showing that this high risk group, the elderly group that up until now we've been less aggressive in terms of blood pressure lowering seem to have benefit. In terms of significant or severe adverse events. There were no significant differences in all cause. Severe adverse events by treatment group. However, the intensive group did have higher rates of hypotension, more syncope and more elevations of seum creatinine evidence of acute kidney injury. So not to be taken likely. So here we summarize the impact of these trials on both the AHA ACC guidelines versus the European guidelines, and you can see some of treatment goals outlined here. For example, office clinic blood pressure, according to the American guidelines are recommending treatment for systolic blood pressures greater than or equal to 130 for systolic greater than or equal to 80. So as we discussed because of the Accord trial that that that goal is a little bit less intense, particularly in diabetic populations where it's 140 and 90 here. So a little bit of controversy remaining in terms of how different groups approach the aggressiveness of treatment. Again, these are the guidelines as of 2017 influenced by the trials we just discussed. Again, we define elevated blood pressure now as systolic 120 to 129 stage one hypertension 130 to 139 for systolic 80 to 89 for diastolic and stage two hypertension greater than 140 or greater than 90. So with stage one or stage two hypertension, we always recommend non pharmacologic interventions but we would also consider starting anti hypertensive medication. When when doing so we're going to consider underlying comorbidities cardiovascular disease diabetes, the presence of kidney disease, and also the pooled risk. Cardiovascular risk, which the guidelines use a cut off of about 10%, and if you have one of these comorbidities, you're going to aim for a treatment goal of less than 130 over 80. If you don't have these comorbidities, you might still consider a treatment goal of less than 130 over 80. So notice how the current guidelines introduced the concept of cardiovascular risk into the decision making of how aggressive to be with blood pressure. This is again new, since all the previous guidelines. Given this more aggressiveness, it has an impact on how we define hypertension. So if we compare the prevalence of hypertension, we would say based on 2014 guidelines, the prevalence is about 32%, but now based on the stricter definition of hypertension. In 2017, the prevalence of hypertension is about 45%. We're going to recommend treatment now to about 36% of people versus 2014 where we would recommend it to about 30% of individuals. The potential events cardiovascular events prevented based on the 2017 guidelines is 610,000 versus 270,000 in 2000 in 2014. The potential total deaths prevented based on 2017 guidelines is 334,000 versus 177,000 in the 2014 guidelines. However, nothing is free. The 2017 guidelines might lead to an increase of hypotensive events upwards of 62,000 per year or acute kidney injury by upwards of 79,000 per year. In a study by Adam Bress in 2017, he projected that with aggressive blood pressure control to a treatment goal of 120, we can avert approximately 107,500 deaths annually in the United States. But with an incremental increase in serious adverse events upwards of 56,000 hypotension episodes upwards of 34,400 episodes of syncope electrolyte disorders which typically hypokalemia hyponatremia hypomagnesemia in upwards of 43,400 and acute kidney injury in upwards of 88,700. So we clinicians are faced with a dilemma. While there are significant reduction in cardiovascular events and death from intensive treatment, it comes with a price and the price are these adverse events. And so that brings us to the definition and the title of my talk which is the treatment risk paradox in blood pressure management. In other words, the reluctance to aggressively lower blood pressure in those at most risk due to the potential for adverse events. Thus patients at higher risk and with the greatest potential to gain from treatment receive less intensive treatment than patients at lower risk and there's the paradox in cardiology we've seen this before this is not the first time. We saw this with using anti coagulation for atrial fibrillation. And so we know there was the development of the Chad's VASC score and as a result of that, we started to be more aggressive in anti coagulating older people. We've seen this in lipid management as well. So this paradox tells us that we need methods that integrate both individualized risk with routine clinical care so that we can better address how we're going to overcome this paradox. We need to be alerting clinicians to each patient's potential benefits from treatment. And this may enable a more patient centered, more evidence based, more efficient care with the overall safer, better outcomes. So hypertension goals. Where are we now? Well, based on what we've learned so far we know that intensive lowering of blood pressure lowers rates of cardiovascular mortality and morbidity in the general hypertensive population, including the very elderly. However, this may not apply to all populations, an example being the diabetic population as we saw with the Accord study. We know that intensive lowering of blood pressure increases rates of potential serious adverse events. So one potential strategy to help guide us from intensive treatment at an acceptable level of risk would be able to stratify populations by their risk of cardiovascular events. So this stratification might identify a particular group of patients who would benefit the most from intensive treatment, but with an acceptable level of risk for adverse events. A history of this, I think a good example would be lipid management, as well as blood pressure treatment. So prior to 2013 prescribers aimed for specific LDL goals, LDL of 160 LDL of 130 LDL less than 100 or aggressive LDL management to 70. The 2013 ACC and AHA guidelines changed this focus, not so much to the actual LDL goal, but more toward the intensity of statin therapy based on an ASCVD risk. So it was recommended to use moderate statin therapy if the 10-year ASCVD risk was greater than 5% and consider an intensive statin therapy if the risk was greater than 7.5%. And this is without quoting a specific number goal for LDL cholesterol. The 2018 adaptation of lipid guidelines tried to incorporate both risk and LDL cholesterol goal into the intensity of treatment. You know, this is to take into account how clinicians think about treatment, making it a little bit easier for us to kind of discuss goals with our patients. So cardiovascular disease risk calculators are easily accessible. These are two examples of them. The one on the right is I took from my health system at Northwell. It's built into the electronic record. You plug in the patient's age, gender, ethnicity, total cholesterol, HDL cholesterol, systolic blood pressure, and then questions of whether or not the patient is under treatment for hypertension, whether they're diabetic and whether they smoke. And after plugging that in, you get a calculated 10-year risk score, and often they'll also give you a comparative risk score to an individual with optimized risk factors. And based on this, we can get some clinical information on our patient. And if we look at a plot like this, we've seen this with lipids, and now we're seeing it with blood pressure control as well, that as we aggressively lower blood pressure, we see less cardiovascular events. But a factor that we have to take into account is the patient's underlying risk of cardiovascular disease. So we see here in a patient with a low ASCVD score, there is some degree of benefit with aggressive blood pressure lowering. But that benefit seems to be significantly more when the underlying cardiovascular disease risk is 16 to 21% or greater than 21%. As you can see, the steepness of these changes as we lower systolic blood pressure compared to patients who have lower cardiovascular disease risk. So the impact of cardiovascular risk on the relative benefit versus harm of intensive treatment of blood pressure was addressed by trials that were based on the sprint population. Back in 2018 or 2017, the New England Journal opened up the sprint database to allow investigators to ask questions about this population. And so I was fortunate enough to participate in a group that was headed by Dr. Robert Phillips, who many of you know down in Texas, as well as the individuals quoted at the bottom here, including myself, did an analysis where we stratified subjects from the spin trial into quartiles based on their 10 year cardiovascular risk. We applied a statistical approach to these patients. It was a Cox proportional hazards model to examine the associations of treatment with primary outcome events, and with serious adverse events. It was a complex process. Statistically, in this study, we use the multiplicative Poisson regression, which is a predictive model developed to determine a benefit to harm ratio as a function of cardiovascular risk. And so you can see here that if you look at these quartiles of risk, the first quartile being the lowest risk and the fourth quartile being the highest risk, and look at participants experiencing primary outcomes based on the sprint trial. You can see that there is an increase of events in both standard treatment in red and an intensive treatment individuals in green, that they all increase as you get into these higher cardiovascular risk quartiles. You can see that there's a bigger spread over here than there is over here, which means that there is a big, bigger difference in protection from primary outcomes in the intensive treatment group who are in this higher risk cardiovascular risk. If we add to that plot a significant adverse events, which we see here, we see here that there's not a dramatic difference between serious adverse events in the standard group which is red versus the intensive treated group in green throughout the quartiles. However, the difference between the two actually turns out to be less in the higher risk group. So when you combine the improved benefit with the with the low difference of serious adverse events, you get this blue curve here, the benefit to harm ratio, where we see in this area here, a significant benefit over harm versus this group here, where we see perhaps more harm than good. And so in the third and fourth quartile of cardiovascular risk, we see improved benefit to harm as risk increases. And so in our trial, we were able to divide patients based on risk with a dividing line here at about 18.2% cardiovascular risk. And those who had ASCVD risks less than 18.2% had a benefit to harm ratio that showed that treating aggressively did not necessarily have more improvement than harm. But if you looked at patients who had an ASCVD risk of greater than 18 to 18.2%, they had greater benefit than harm with intensive therapy. A nice clear division here where you use the ratio of benefit to harm ratio of one as your divider. And you see here, these groups are less than one, and these groups here are greater than one. So the implications of this are quite significant. Because if you remember the guidelines from 2017 told you to look at a 10 year risk of 10%. And that to consider more aggressive treatment at that 10% threshold. Whereas in the analysis of the sprint trial that we did shifted that up to a threshold of about 18.2%. So those with less than 18.2% would fare better with the usual treatment goal of 140. And then those with cardiovascular risk more than 18.2% would do better with more aggressive blood pressure management. And this is significant because upwards of 10 million Americans have 10 year risk between 10 and 18.2%. So our analysis of risk has an impact on approximately 10 million individuals. It was controversial when this data came out. But what is comforting to know is that in March of this year, 2021, Adam Bress and his group did another, did a sub analysis of the spin trial, and they used a different statistical approach than the one that Dr. Phillips and his group used. But having used their approach, they showed similar finding. They showed that that in higher quartile risk groups, if you compared standards therapy in this case a solid line versus intensive therapy which is a dashed line that the cumulative incidence of cardiovascular events dropped considerably in the higher risk quartile groups compared to the lower quartile groups. They also showed increased adverse events as you went into higher risk groups. But again, that difference as you got into the higher risk groups became less striking between the intensive and less intensive treatment groups so that the overall benefit, the overall benefit compared to harm was significant in these higher risk groups. So this is a little summary from Bress's group showing again that in higher risk patients, there was a higher tendency to have adverse events, just as in the low risk groups, low probability of having intense events, but as you got to higher risk cardiovascular event groups, aggressive therapy, the benefit you got for reducing cardiovascular events outweighed the harm from adverse events. So putting all this together, how do we treat our patients? How do we address this? Well, we see that organizations including the American College of Cardiology, the American Heart Association, the American College of Physicians, and the American Academy of Family Physicians are moving towards incorporating cardiovascular risk stratification in patients for the treatment of hypertension, as we are already doing for treating lipid disorders. If large increases of serious adverse events such as acute kidney injury, hypotension, syncope and falls are clinically important as relatively small reductions in heart failure or cardiovascular mortality, then one may not aggressively treat patients with lower overall cardiovascular risk. But when we are dealing with our high risk patients, we are learning that we may have to change our practice to meet these goals and intervene early on the potential adverse events. So if you have an older patient that you want to aggressively treat blood pressure, you may have to see them more frequently in the office to assess for orthostatic hypotension. You may want to arrange for telemedicine visits to review medications, to review self-obtained hemodynamics as more and more people are purchasing blood pressure machines and measuring blood pressure at home. And we know that these self-obtained readings are accurate. You may need to obtain more frequent laboratory assessments for hypokalemia, hypomagnesemia, elevations of serum creatinine. And again, as we change our approach to these patients, we may have to consider the rapidly changing healthcare payment and delivery model in this country as we see. So with that, I'm going to end my talk and I want to thank you for your attention to this. And again, I really enjoyed participating in this conference with you. Thank you very much.