Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Donna M. Polk and Dr. Michael P. Dorsch. This program is available as read only and with accompanying audio. If you are unable to access the audio portion of this presentation from your computer, this activity is also available on demand as a digitized replay via the telephone. To listen to the presentation, dial toll-free 800-642-1687 and enter activity code 26634208.
To complete this educational activity, the post-test can be accessed via the Program Components menu or the Testing Center link on the Princeton CME home page.
*Scroll to read lecture and/or follow along with audio.
Slide 1: Welcome to the teleconference, “Comorbidities of Uncontrolled Hypertension: Reducing Risks and Burden.” This program is supported by an educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.
My name is Donna Polk, and I am from Cedar Sinai Medical Center in Los Angeles. I will be your presenter along with Dr. Michael Dorsch, who is Clinical Pharmacist in cardiology and Adjunct Clinical Assistant Professor in the Department of Pharmacy Services at the University of Michigan Hospitals and Health Centers in Ann Arbor, Michigan.
Dr. Dorsch will be presenting a case study which will apply the data presented to a real-world scenario. Please note that all faculty disclosures for this program are included in the front of your activity booklet.
Slide 2: My goal in speaking to you today is to help you identify patients with hypertension who are at high risk for associated comorbidities that include diabetes, kidney disease, dyslipidemia, myocardial infarction, and stroke so that we can identify those patients and prevent the progression of these comorbid conditions, as well as to evaluate the long-term economic burden, and also to look at strategies for pharmacologic management to reduce the consequences of uncontrolled hypertension.
Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation. These forms are located in the back of the activity book. You can also complete those online to get immediate receipt of credit, and the Web site is www.princetoncme.com. So, thank you again for joining us. Dr. Dorsch will now introduce the case study.
Slide 3: Thank you, Dr. Polk. We are going to start off today with a case presentation.
Slide 4: JD is a 68-year-old male with diabetes. His blood pressure has been difficult to control despite multiple medications. In the past they have not tried ACE inhibitors because of borderline hyperkalemia. Except for very mild exertional dyspnea, he has been asymptomatic, although he reports episodes of pedal edema after prolonged dependency. Today he has not taken his water pill because he wishes to avoid urination during his medical visit. His medications are hydrochlorothiazide 25 mg/day, atenolol 50 mg bid, hydralazine 50 mg 4 times a day, clonidine 0.2 mg bid, fluticasone, albuterol, and he also takes insulin glargine.
Slide 5: His past medical history—he has asthma, hypertension, and diabetes. His family history is difficult to obtain because he is adopted. Social history—he smokes half a pack of cigarettes per day. On physical exam, he has mild obesity; he sits and has a blood pressure of 180/115 mm Hg and a pulse of 90. On HEENT exam, he has hemorrhages and exudates in the ocular fundi. On lungs exam, he has soft rales present at the lung bases, and he has faint expiratory wheezes where appreciated. Cardiovascular exam—he has jugular vein distension to 8 cm above the sternal angle. He also has a fourth heart sound and hepatojugular reflex. Abdominal exam was normal. Extremities—he has diminished pulses and 2+ pitting edema halfway up the knee. Exertional dyspnea due to asthma in the workup was negative.
Slide 6: As far as his ECG, it shows evidence of LVH but no prior infarction. Chest x-ray shows pulmonary vascular redistribution and normal heart sound. And looking at his labs, he has a BUN of 31 mg/dL, a creatinine of 2.0 mg/dL, resting blood glucose 102 mg/dL, HbA1c 6.7%, sodium 130 mEq/L, potassium of 4.9 mEq/L, and his urinalysis showed 2+ protein and 2+ glucose.
Slide 7: Just overall looking at this patient, why is JD not reaching his blood pressure goal on his current medical regimen? And also, what steps should be taken to attain his blood pressure goal?
I will now turn things back over to Dr. Polk for her presentation.
Slides 8 and 9: So, first we will talk about the prevalence of hypertension.
Slide 10: In the first slide you can see that the prevalence is quite high for hypertension. The lifetime risk for an individual is greater than 90%, and nearly 1 in 3 American adults have hypertension.
The risk really begins at a fairly low level, if we think about what our goals are for hypertensive management. The risk for cardiovascular disease doubles for every 20/10-mm Hg increase in blood pressure from a level of 115/75 mm Hg. So, really quite low does our risk go up in these patients. So, if we think of a goal of 140/90 mm Hg, we are leaving a lot of untreated risk in our patients. Most patients need greater than 2 drugs to really even achieve a target of greater than 140/90 mm Hg, and often need 3 drugs if our goal is to have their blood pressure even lower.
Slide 11: The prevalence is quite extensive in the United States, and in the next slide you can see the prevalence is going up considerably. In 2004, the number of patients who had hypertension in the United States was 72 million, or 33% of our population. If you look at just a few years before, it was 65 million. So, as our population ages, the prevalence of hypertension is only going to increase and will really be a foundation of our patient care.
Slide 12: On the next slide you can see some NHANES data, which is really a snapshot of what our population looks like at any one time. And you can see by this slide that hypertension is an age-related disease. The prevalence of hypertension goes up dramatically with age, and you can see by the time patients are 75, almost 84% of women will have a diagnosis of hypertension and over two thirds of men. So, as we age, the prevalence is going to go up; and again, as our population ages we will only see more and more hypertension.
Slide 13: And if you look at the mortality from that hypertension, it is quite prevalent. If you look at the number of people whose mortality was attributed to hypertension, it was over 50,000 just in 2004. In those 5 years preceding that, if you look at the age-adjusted rate just from hypertension, it increased 25% and the number of people that died secondary to hypertension rose over 50%.
And if you look at the overall death rate from hypertension, 18% in our population and disproportionate in the African American male and female populations who had almost up to 50% mortality attributed to hypertension; so, clearly a lot of mortality that we can intervene on by treating hypertension early.
Slide 14: So, let's just then look at identifying and reducing risk factors of hypertension.
Slide 15: If you look at just how we initially look at a patient, we are going to see these patients at a variety of different stages in their life. It is more than just taking a simple history and physical looking for symptoms and signs of end-stage disease, but also looking for how that patient is going to take their drugs. Who is in their environment? What else is going on? We think a lot about noncompliance, or inability to be compliant with medications, for a variety of reasons.
So, it is important to understand those in any patient that we look at to try to effectively treat their hypertension. We also need to look for evidence of end-organ damage as well as secondary causes of hypertension; any physical clues that could help us with that. And they obviously need a thorough laboratory evaluation—electrolytes, renal function, and urinalysis—as well as an electrocardiogram to look at end-organ damage.
Slide 16: If you look at how we should approach these patients, obviously again starting with the history, physical, and laboratory evaluations, but really looking for complicated or secondary hypertension. If there is not, then that is easy; we can just start therapy. If there is, then we need to tease out a little bit more of trying to look for target-organ damage. Is there something that is reversible that is a secondary cause of hypertension? How can we manage that, and hopefully reverse the hypertension and not subject that patient to life-long, antihypertensive therapy?
Slide 17: If we look at risk factors for hypertension, they are quite extensive and you know many of these. These are quite prevalent in our population—obesity, smoking, sedentary lifestyle, excess salt, alcohol, and stress—as well as things about the patient, such as ethnic background or family history, that are important risk factors for hypertension that we clearly need to look at and identify so that we can at least include those when we treat the patient.
Slide 18: Hypertension does not just live by itself; it often comes with several other risk factors. And if you look at the next slide, Cardiovascular Risk Factors and Hypertension, it is only a minority of patients that just have hypertension. You can see in the males only 19%, and in the females 17%, only had evidence of just hypertension. The majority had at least 1 other risk factor, and up to 4 other risk factors.
So, it is very, very common for these patients to have multiple comorbidities for cardiovascular disease; all the more reason for us to be aggressive in how we treat their hypertension. And as you can see in the next example, looking at all of these risk factors together and how they interplay is very important.
Slide 19: Here is, for example, a 10-year risk of vascular disease, and looking at the importance of systolic blood pressure in a variety of different patient scenarios. If you look all the way on the left-hand side, here is the lowest risk individual: somebody whose cholesterol is 180 mg/dL, HDL is 50 mg/dL, nonsmoker, nondiabetic, no evidence of LVH. They have the lowest risk. But even in that low risk, you can see having a blood pressure less than 120 mm Hg puts that person at much lower risk. As you start increasing those risks—so look at the next one—just a little higher cholesterol, same HDL, again nonsmoker, nondiabetic, that risk goes up. And as you make the profile a little worse and a little worse, that risk goes up. And if that patient has LVH—clearly the highest risk, that you can see on the right—just having LVH puts that person at significantly higher risk. So, knowing that there is end-organ damage is very important in looking at our patients' cardiovascular risk. And you can see in each level of comorbidities and corisks that blood pressure that is under control and not under control adds significantly to the 10-year risk of cardiovascular disease.
Slide 20: The next slide looks at a similar scenario in looking at 10-year risk for stroke. So, the previous was cardiovascular disease and this is stroke, and you can see again how important systolic blood pressure is as a risk factor. As that blood pressure goes up with each increment, you can see how much higher the risk is. Look how high it gets in the older women. You can see that risk goes up significantly, and this is a 10-year risk for stroke. Diabetes makes a difference, cigarette smoking makes a difference, atrial fibrillation, and prior history, but it is really the blood pressure that is driving that risk, both in men and women.
Slide 21: If you look at the risks of cardiovascular comorbidities, that risk and prevalence of hypertension in a lot of different scenarios is really important. Two thirds of people have a first MI, 77% have the first stroke, and 74% with heart failure have had blood pressure that is elevated or had a reading that has been 140/90 mm Hg. So, it really precedes the cardiovascular comorbidities and mortalities that we see.
You can see people with systolic blood pressures of 160 mm Hg or higher and a diastolic above 95 mm Hg have a relative risk for stroke that is 4 times greater than those with normal blood pressure. So, clearly that risk is important for stroke as well as cardiovascular disease.
And if we look at patients who have heart failure—clearly something that we know is linked to hypertension—91% have had hypertension as a previous diagnosis prior to their development of heart failure. Those patients have a 2 to 3 times higher risk of having heart failure; so, clearly linked to a lot of comorbidities that we would like to prevent.
Slide 22: Let's shift and look at the economic burden of not treating hypertension and what that looks like.
Slide 23: Here is the number of outpatient and ambulatory care visits, and you can see the number of instances of hypertension was over 45 million. So it is a very prevalent reason for patients coming to see a healthcare provider. This is from 2001 to 2002; and as I told you before, as that prevalence increases, then these visits are only going to go higher.
Slide 24: And if you look at what is driving the cost of care, looking at both the direct and indirect cost of cardiovascular care, as you are not probably surprised, drugs and other medical durables are what is really driving that. It is not so much the visits, or even the hospitalizations, but the pharmacologic therapy that is driving it. As you can see here, heart disease, hypertension, hypertensive disease, and cardiovascular disease are really driven by drugs as the primary cost of care.
Slide 25: And if you look at the cost of treating hypertension, and this looks at an estimated cost for this year, indirect cost of treating hypertension is over $66 billion. If you look at total direct costs, it is almost $50 billion. So, if you think about the amount of healthcare dollars that are going towards hypertension, it is really quite dramatic.
Slide 26: If you look at the annual cost per person with hypertension and the attributable cost to hypertension, it is really quite prevalent across the pair. Whether it is an older population or Medicare population, in all pairs it is really a large portion of what the annual healthcare costs are per person. So, it is incredibly important for us to think about how we treat our patients with multiple therapies, to try to be cost-effective with how we choose to treat our patients and what drugs we end up using.
Slide 27: And if you look at the next slide, it looks at total expenses for hypertension by site of service. This is in 2004, so again a few years ago, you can see medications driving that cost. So, this is a really important component of how we are looking at healthcare dollars.
Slide 28: The next slide looks at the risk factor clustering and cardiovascular disease in hypertensive patients. This was a study looking at almost 60,000 patients from Kaiser Permanente Northwest, and all of these patients had no evidence of cardiovascular disease but were hypertensive. They needed to be above the age of 35. They then were risk stratified into 8 different risk factor clusters, and then followed over time for cardiovascular events. And then they looked at what were the healthcare costs per patient of those individuals over the 6 years.
Slide 29: What you can see is that those healthcare costs really were driven by comorbidities, by diabetes. So, if you have diabetes and hypertension, that healthcare cost goes up dramatically. So, you can see looking for comorbidities, figuring out how to best identify our patients, will help us at least identify who is at highest risk as well as highest cost, so that we can be a little more effective about how we treat those patients.
Slide 30: So, let's shift now to the issue of adherence.
Slide 31: This is something that challenges us every day in our clinical practice; that we struggle with patients who are not at goal, trying to figure out why they are not at goal. This first slide is the extent of awareness of treatment and control of hypertension. This looks at different races and ethnicities, trying to say, how good are we at treating our patients?
This again looks at a snapshot of patients, looks at awareness, treatment, and how many are controlled. A lot of people know they have hypertension. They are often on treatment. In fact, you can see the next group of treatment, and then how many of those who are even on treatment are controlled. And you can see it is a fraction. If you look at the Mexican Americans, only 25% of patients who have hypertension—so these are patients who have a measurement of hypertension—are controlled. So, clearly a big gap between who is controlled and awareness.
Slide 32: If you look at the next slide with the pie graph, and look at characteristics of patients who have uncontrolled hypertension, these patients are not just sitting out there at home. They are coming and seeing their physicians. Ninety-six percent of these patients, who were surveyed in this NHANES kind of snapshot of our US population at any one time, 96% said they saw a physician at least once, if not more than once, in the last year. Seventy-seven percent had an elevated blood pressure greater than 140/90 mm Hg, and most of those patients saw their physician more than once. You can see the treated and controlled blood pressure, down in the bottom center part of that pie, is really a fraction. Half of them either were unaware or aware but were not even on treatment, and then a portion were treated but not controlled. But it was really just a fraction that were treated and were at the appropriate blood pressure. So, there really is a big, as I said before, gap between what we are able to do and where our patients are at. So, actually, a wonderful opportunity to do a lot more risk reduction and prevention of cardiovascular disease if we are able to identify these patients and treat them more effectively.
Slide 33: So, how do we get to goal? You can do it through step-care, so that you can just keep titrating up that single medicine to a higher dose to get to your goal. You could do sequential treatment, adding a second agent and going on that way. But the reality is most of our patients need more than 2 drugs just to get a blood pressure less than 140/90 mm Hg and greater than 3 to get a blood pressure of less than 130/80 mm Hg. So really, whatever approach you are comfortable with, there is data that shows that both a step-care and a sequential approach are effective. But if you know that your patients are going to need more than 2 drugs, being aggressive up front is probably the most appropriate treatment strategy.
Slide 34: Well, why are our patients not at goal? So, we always say, well, they are nonadherent. It is important to understand why they are nonadherent. They may not understand what their goals of therapy are. If you tell them that their stroke risk is higher, then patients are often amenable to taking drugs if they think their stroke risk may be reduced as opposed to just having a heart attack. They may not understand the nuances of the medicines and how they should be taken. Sometimes they feel as though they are not involved in those decisions about how they are paying for their drugs and how they are taking their drugs. So, even involving a patient may help with response to therapy. Patients have white coat hypertension. Some patients, as they age, may have more difficulty with memory. They may need other mechanisms to help them remember their blood pressure; and again, sometimes we just need to recognize that there is volume overload as one of the ideologies for high blood pressure.
Slide 35: Well, what are some of the drug-related causes about why patients have lack of response to therapy? There may be side effects, and they may not be willing to tell you about the side effects unless they are approached and asked about it. We may not be adequately dosing them; they may be subtherapeutic. It may be an inappropriate medication that is not appropriate for that patient's condition. Cost, clearly an important reason, why patients may be splitting their medicines, may be taking them every other day, or may just be not filling their prescription at all, because of concerns about cost. Patients may not be taking it because it is a TID dosing. Most patients cannot remember to take drugs 3 times a day. They may not have understood completely their instructions. There may be inappropriate combinations as well as drug interactions that may be responsible for patients' lack of response to appropriate pharmacologic therapy.
Slide 36: So, we really need to spend time and really focus on techniques to help patients adhere to pharmacologic therapy. We need to encourage them to really talk about it. What are their barriers? Why are they not able to take their medicines? Is it cost? Is it timing? Is it the side effects? We really need to spend that time with each of our patients to really ask them what is preventing them from taking the medications. I often ask my patients how many times a week they cannot remember to take their meds or they forget to take their meds. It allows them to realize that they can’t even tell you that they are skipping meds, and try to find out the reasons why and try to find out ways for them to be more adherent. Having patients follow their own blood pressures at home often gives them some control about their treatment plan, but also allows them to see the response to changes in medical therapy or changes to exercise, and so they feel a little bit more involved in their treatment plan.
We really need to simplify regimens; qd dosing is clearly the best approach if we are able to maintain a blood pressure control on that, and giving patients information to take home with them. They may not hear everything you tell them when they see you in the clinic or in the office, but taking stuff home so that they can refer to it is important. Patients may just do better with pillboxes. They may be able to be more adherent, particularly as patients age or have difficulty remembering.
Slide 37: So, let's just shift to talk about the treatment of patients who have comorbid conditions.
Slide 38: We talked about the increased risk of cardiovascular disease, and our real goal is to reduce cardiovascular disease, morbidity, and mortality. That is really what we are doing.
We are also trying to prevent target-organ damage, LVH, subsequent heart failure, stroke, kidney disease, peripheral artery disease, and retinopathy. We are really trying to prevent the morbidity associated with hypertension by preventing end-organ damage. Really, our goals for everybody should be a blood pressure of less than 120/80 mm Hg, and particularly important in our diabetic patients to make sure that their blood pressure is less than 130/80 mm Hg. And if you look at the goals, those are the goals for patients with diabetes or chronic kidney disease.
Slide 39: On the next slide are compelling indications for individual drug classes. We are often struck by what drugs do we start with and who is appropriate? The ALLHAT data really drove what the JNC 7 guidelines told us: to start with a diuretic. That is often a good basis and a foundation for how we treat patients, but again remember most patients are going to need 2 and 3 drugs.
So, we often look for other reasons to give certain drugs, and you can see on this table for reference, that if you look at the comorbidities or the disease states, that there are a variety of choices for patients about which drug class is appropriate for hypertension control. We will go through those a bit at a time. But it really is a broad range of choices, and we should think about combining the best of a couple of them if we are treating our patients, particularly if they are much more hypertensive than their goal and we have a lot of room to give additional medications.
Slide 40: So, if you look at the next couple of slides—look at these broken out—for heart failure, there is clearly good evidence for diuretic therapy, beta blocker, ACE, and ARB therapy as well as aldosterone antagonist. You can see there are a lot of clinical trials to the right of the chart. For post-MI, there are good reasons for beta blocker, ACE inhibitors, and aldosterone antagonists. For patients at high coronary disease risk, again, there are a lot of classes of drugs that are appropriate for this group of patients.
Slides 41 and 42: The references are here for you on the next slides.
Slide 43: For patients with diabetes, there are beta blockers but also ACE inhibitors and ARBs; and we will talk in a bit about some of the trials that really support treatment of diabetics with these classes of drugs. Again, for chronic kidney disease, ACEs and ARBs are a real foundation of therapy. So, for somebody who has renal deficiency, to start them on an ACE or ARB as the initial therapy may be very appropriate for a new hypertensive patient. For patients with recurrent stroke prevention, ACE inhibitors or thiazide have been shown in the PROGRESS trial.
Slide 44: Again, the next slide shows you those references.
Slide 45: So, let's pull out a little bit more of each of these compelling indications for hypertension therapy. For heart failure, really there is a multiple modality. We are often limited by how we can treat our heart failure patients because of hypotension, so we try to give a little bit from each of these classes. There is good evidence for ACE inhibitors, ARBs, aldosterone antagonists, and beta blockers; all have been shown to decrease cardiovascular risk. For beta blockers, there are certain ones that have been shown in patients with systolic heart failure to improve morbidity and mortality. Patients should be more euvolemic and more stable before they get beta blockers titrated or initiated. We usually start at fairly low doses as, again, as often these patients are very hypotensive if they have very bad heart failure. ARBs and ACEs are also good in this population. Spironolactone has been shown after standard therapy to be associated with reduced cardiovascular risk; so again, a very important drug class not to forget in this population.
Slide 46: How about post-MI? We often think of beta blockers, and indeed they do minimize the risk for recurrent MI. ACE inhibitors are also helpful in this population, particularly in patients who have had LV dysfunction from their MIs. There is a new study looking at aldosterone antagonist. It is also able to reduce mortality in this post-MI population, but be aware that that can also cause hyperkalemia, and if you have already given an ACE in this population, you need to watch that very carefully.
Slide 47: How about those patients at high risk for coronary disease? Such as patients with angina, with known angina. There are beta blockers or we can use calcium channel blockers; we tend to prefer beta blockers as the initial therapy. There is good evidence in ACE inhibitors in the EUROPA trial; reduced cardiovascular disease by 20% in addition to standard therapies. For patients with acute MI or unstable angina, beta blockers and ACE inhibitors certainly have been shown to improve mortality. We need to be careful about beta blockers, at least acutely in an MI setting, as that may worsen outcomes. But it is certainly around that time that you need to think about beta blockade.
Slide 48: How about diabetics? This is a large population that you will see. The initial drug therapy for hypertension—we will talk about in a minute—about several of the studies supporting the use of ACEs or ARBs. Also, diuretics and beta blockers can be appropriate in this population. For patients who have evidence of renal dysfunction or who have evidence of albumin in their urine, ACE inhibitors and/or an ARB are appropriate in this setting. For patients, again, with nephropathy or renal insufficiency, we do not avoid ACEs; in fact, we give ACEs to these patients. Patients at high risk, we often think about an ACE inhibitor as well.
Slide 49: For patients with chronic kidney disease, there is good evidence that treatment reduces the progression to end-stage renal disease. These are patients who have a GFR far less than 60 mL/min/1.73 m2. You may not think that is evidence of bad renal disease, but indeed it is. Their creatinine is greater than 1.5 mg/dL for men or 1.3 mg/dL for women. That is evidence for renal dysfunction. And then again, if they have albumin in their urine, there is evidence of chronic kidney disease. So, their goal is to have a lower blood pressure; less than 130/80 mm Hg should be your goal. ACEs and ARBs are really the preferred treatment because they will dilate the efferent arteriole of the kidney, decrease the glomerular pressure, and lessen the progression to end-stage renal disease. So, it is a group that we really want to be aggressive about treating with ACEs and ARBs
Slide 50: Well, what about how much therapy people need? If you look at, and as I mentioned before, most patients are going to need 2 if not 3 drugs. If you look at just monotherapy, how many patients are going to get treatment with just monotherapy? You can see about half the patients placed on thiazides will make it, calcium channel blockers 40% to 60%, central and alpha blockers only a third; so if you look, there is no group or class of agents that is going to get you effective therapy by itself.
Slide 51: So, you are always going to need 2 agents. You may just start up front with 2 agents, or you may just have a very low threshold for going on to a second agent. Lots of trials, and we will go through some trials in a bit, but most trial patients needed 2 agents to get a blood pressure less than 140/90 mm Hg and 3 to get less than 130/80 mm Hg. As we talked about before, a diuretic is often the basis of it and then you add a second agent. So, if a patient's blood pressure goals are not anywhere near being met, your blood pressure goals are greater than 20 systolic or greater than 10 diastolic, you are going to need 2 drugs. It may be an appropriate way to start both at the same time.
Slide 52: Well, what are the benefits of blood pressure control? Well, we have lots and lots of trials, and in the ‘80s and ‘90s we did placebo-controlled trials. Those trials allowed us to say, not only was treatment of blood pressure effective, but it also reduced mortality and morbidity. You can see 35% to 40% reductions in stroke, 20% to 25% reductions in MI, and a 50% reduction in heart failure, and those were in the placebo-controlled trials.
So, we were not able to do placebo-controlled trials after that because the benefit was so great that it was unethical. So, many of the drug trials now are shifted to see if there are class differences or drug-specific reasons to treat people with certain classes of drugs. And if you look at how many patients do we actually need to treat to be effective, we will often look at the number needed to treat, or the NNT, as the basis of how effective or how appropriate certain drug therapies are. And if you look at the number needed to treat their hypertension over 10 years, and that is reducing the systolic blood pressure by only 12 mm Hg, so not that much. How many needed to be treated to save 1 person, so to prevent 1 death? For primary prevention, somebody who is at higher risk and has other risk factors, only 11; and for secondary prevention, only 9. So, really the benefit from treating patients, we do not have to treat very many patients in our practice over time to really see the benefits of appropriate antihypertensive therapy.
Slide 53: It is important—and I am going to have you look at the next slide, which is from the INVEST trial—it is really appropriate to figure out how well we have treated people over time. This is just an example of outcomes based on how many patients were at blood pressure goal during their visits. So, these are people in a study that were seen, and blood pressure measured periodically over this trial. They looked at outcomes, which were MI and stroke, fatal and nonfatal. You can see under primary outcome, those who were at goal 25% of the time were the baseline. You can see patients who, under primary outcome, who were at goal greater than 75% of the time had the lowest risk; and you can see that, under reduced risk, the more often you were at control when you were seen in the office, the better your outcomes were.
So, it really is about making sure each and every time we see our patients we figure out, are they at goal? Why are they not at goal? What can we do to help them be at goal? And you can see that whether it is MI, or particularly stroke, that the better off their control, the less bad outcomes they will have. So, it really is about consistency over time.
Slide 54: So, let's just shift now to some landmark and recent trials, and then I will finish by telling you about some ongoing trials that will help us hopefully better identify which drugs we should use in which populations, and which combinations in particular.
Slide 55: One of the big arguments and points of discussion in hypertensive therapy is, is it a blood pressure effect or is it a class of drugs effect? And which is the one that is most important? It is probably both, and I will start by just talking about the INVEST trial, which looks at verapamil versus atenolol, 2 different drug classes against each other, to see which one was more effective. Were they the same in reducing all causes of mortality, nonfatal MI, or stroke? They looked at a large population, over 22,000 men and women, who were above the age of 50 who had hypertension and heart disease. They really wanted to have a group of patients that really look like the patients that we see each and every day, with people with diabetes, women, elderly, to really try to reflect the real world.
Slide 56: What they found is that both of these drug treatment regimens had the same amount of blood pressure control, and they also reduced the same amount cardiovascular deaths and cardiovascular hospitalizations; so, same blood pressure, no difference. The verapamil group did have a little bit lower incidence of new-onset diabetes, but I can show you several different trials that showed similar outcomes based on different classes as compared against each other.
Slide 57: So, then the question becomes, is there evidence that there are some classes that in certain settings may be more effective depending on what your end point is? And we are going to shift and look at several of the ARB and ACE trials to sort of look at that.
The first is the RENAAL study that looked at patients, and their end point was doubling of serum creatinine, end-stage renal disease, or death. They looked at a large group of individuals, followed them, and looked at their renal function over time. What you can see is that the primary composite end point was significantly reduced, but really what was driving that reduction was not death but the progression to end-stage renal disease and the doubling of serum creatinine. So, it was really the renal outcome that was driving the end point. So, in this population there was evidence that the end point of doubling of serum creatinine and end-stage renal disease was important reduction from ARB therapy.
Slide 58: What you can see on the secondary end point: were there other individuals that benefited from ARB therapy? There was a 10% risk reduction in the secondary composite end point for first hospitalization to heart failure. So, there was less heart failure in the group that was treated, a third reduction in the amount of proteinuria that was found in this population, and a reduction in the decline of renal function. So, these patients' renal end points improved significantly with treatment with an ARB.
Slide 59: The IDNT was another trial looking at diabetics. They pulled out specifically diabetics, and looked at over 1700 of them who had evidence of hypertension, but evidence also of nephropathy. So, they had proteinuria and a serum creatinine between 1 and 3 for women and between 1.2 to 3 in men; so, evidence of end-stage disease at the initiation. So, they randomized patients to irbesartan, an ARB, versus a calcium channel blocker, amlodipine, and looked at how it affected their kidneys.
Slide 60: And what they found, on the next slide, is that patients who were treated with the ARB had a lessening of the primary end point. Again, this was composite of doubling of serum creatinine, end-stage renal disease, or death versus those patients that were treated with amlodipine. And if you looked again, just like the previous trial, the proteinuria was reduced by a third in those patients on the ARB compared to 10% with placebo. So, just reducing blood pressure helped reduce the proteinuria, but treatment with an ARB reduced it even more. These benefits appeared to be above and beyond those that were just related to blood pressure control.
Slide 61: IRMA II is another trial looking at the renal protective effects of ARBs in patients, again with diabetes and evidence of renal dysfunction and hypertension. So, this looked at almost 600 patients who were hypertensive and had persistent evidence of microalbuminuria. So again, these patients have evidence of elevated serum creatinine and albumin in their urine.
Slide 62: Consistent with the other trials, treatment with an ARB reduced the rate of progression from people who had just microalbuminuria to diabetic nephropathy, so that spectrum was halted in a significant number of patients. There was renal protection from irbesartan in patients who had type 2 diabetes and microalbuminuria. It was, again, independent of the blood pressure–lowering effect, so more and more evidence that there is something about the class of drugs, the ARBs, that is effective in this population. And again, in patients with type 2 diabetes and hypertension, there was evidence of renal protection.
Slide 63: Well, many of those trials had patients at maximum doses of ARBs; they were on high doses—the maximum dose. The MARVAL trial looked at a population, and this was a smaller group of patients—it was 300 individuals who again had type 2 diabetes, but they were treated with 80 mg of valsartan, so lower starting dose, or 5 mg of amlodipine. And they looked at it over a fairly short period of time; their target blood pressure was 135/85 mm Hg and they looked at urinary albumin excretion rate, or microalbuminuria, compared with each of the treatment arms. What they found was that the ARB reduced that compared to the amlodipine; and that in fact, some people who had evidence of albumin in their urine normalized. It reduced that protein to the point of normalization in about a third of those patients treated with the ARB versus only 14% of those treated with the calcium channel blockers. This again was independent of blood pressure effects. So, even with the lower dose of an ARB, you may see some reduction.
Well, most of our thought process, and what we do, is really aimed at looking at systolic blood pressure. Well, what about diastolic blood pressure?
Slide 64: This is the HOT trial. This looked prospectively at over 18,000 patients who had hypertension, and they were randomized in a double-blind manner to diastolic blood pressure goals of less than 80 mm Hg, less than 85 mm Hg, or less than 90 mm Hg. They used a whole variety of different regimens to attain their blood pressure, but they looked at cardiovascular events in each of these drug groups. And what they did, is they subgrouped those who had diabetes (shown on the right). So, if you looked at the whole population, it did not seem to make a difference about what the diastolic blood pressure goal was since cardiovascular events were about the same. But in those diabetics, it clearly made a difference about treating the diastolic blood pressure. So, a goal of less than 80 mm Hg produced a clear reduction in events as compared to a blood pressure goal of less than 90 mm Hg. So, in addition to thinking about end-organ damage in our diabetics, we need to think again about how important achieving a diastolic blood pressure goal of 80 mm Hg is for our patients.
Slide 65: So, I am going to end by telling you about a couple of ongoing trials, and hopefully will help answer about combination therapy—what the appropriate treatment regimen is in our patient populations—because there are still a lot of unanswered questions.
The first is called the ACCOMPLISH trial, and that is looking at the effects of treatment with benazepril, so an ACE inhibitor plus amlodipine, and comparing that to benazepril plus hydrochlorothiazide. The end points are cardiovascular morbidity and mortality. This will look at over 12,000 patients for a 5-year follow-up, and looking again for cardiovascular morbidity, end-stage renal disease, or target-organ damage as end points.
Slide 66: They will be looking at a good dose of benazepril 40 mg/day, hydrochlorothiazide 12.5 to 25 mg/day, or amlodipine between 5 and 10 mg/day, and they will be able to be on other antihypertensive medications in order to achieve an adequate blood pressure goal. So, the goal will be to have the same blood pressure reduction; and again, that is an ongoing trial that hopefully will help us tease out what combinations are perhaps better than others.
Slide 67: The next trial is called the ONTARGET trial, and this is looking at combination of ACE and ARB. So, this is looking at an ARB, ramipril, in combination, and looking at whether or not that is more effective than ramipril alone. The end points are cardiovascular death, MI, stroke, or hospitalization for heart failure. And again, this will look at 5-year follow-up for both end-organ damage and mortality.
Slide 68: So, up front patients cannot have heart failure, but progression to heart failure will be one of the end points. And again, this will look at combination therapy and seeing if that is more effective than single treatment with an ACE or an ARB.
Slide 69: So our conclusions are that there are patients who have hypertension that are very often high-risk patients. They have other diseases. I showed you that pie graph that showed that most patients have at least 1 other cardiovascular risk factor. We need to think about patients who come in for treatment of hypertension as high-risk individuals. The cost and burden of hypertension increases as patients have more comorbidities, and will be important in how we decide a treatment plan for patients. There is a good evidence base that we should look at our patients who are at high risk, to look for comorbid risk factors or disease states that we can more appropriately give certain agents to reduce risk. And hopefully, as these next trials come out, we will look at combinations of therapies and try to find the most appropriate combinations for more patients.
Thank you. This concludes my presentation. We will now turn back to Dr. Dorsch for discussion of the case study mentioned at the beginning of this activity.
Slide 70: Thank you, Dr. Polk. And now we will go back and talk a little bit about the case resolution.
Slide 71: So, the patient has hypertension not controlled and some other factors, but that is due to 2 major factors: nonadherence and possibly some secondary causes of hypertension.
So, first we will talk about nonadherence. He does have a complex medical regimen, with many of his medications having multiple times a day. So, if we can, we would like to have them as once-a-day as possible. He also had varying administration times of his medications throughout the day. So, if we could get drugs that are all on 1 time a day, that would be most ideal. I would also like to get the patient involved in his understanding of the disease. We need to get the patient to see if they could understand when to take their medications and how to take their medications, or talk to them a little bit more about when they take their medications, and see if we can tailor their medical regimen to when they take their medications.
A secondary cause of hypertension is also another problem that may be causing his uncontrolled hypertension, so there should be a workup for pheochromocytoma or potentially unilateral renal artery stenosis or bilateral renal artery stenosis.
Slide 72: Some of the recommendations for the management of JD’s hypertension include lifestyle changes, obviously smoking cessation is an important one, diet and exercise, and also promoting a moderate use of alcohol or reducing his alcohol intake. Looking at his medical regimen based on the presentation from Dr. Polk, we would recommend potentially discontinuing the atenolol and discontinuing the hydralazine and the clonidine. We would also probably want to start an ACE inhibitor or an ARB, since the patient has diabetes and has hypertension. Thinking about hyperkalemia, we would probably want to monitor that very closely.
So, monitoring his new regimen, and adjusting as necessary or reevaluating adding other classes, we could think about adding a loop diuretic since he does have some edema. With his creatinine, the hydralazine may not be good enough for diuresis. We may want to think about an ACE inhibitor and ARB combination, since he does have some proteinuria, and also the addition of potentially the calcium channel blocker in the future if his blood pressure is continuing to be uncontrolled.
I would like to thank you for your time, and this concludes my presentation.
