The importance of managing cardiovascular risk in the treatment of hypertension: The role of ACE inhibitors and ARBs

Authors


Charon A. Pierson 915-307-4462; E-mail: cpierson@aanp.org

Abstract

Disclosure: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Each participant received an honorarium from Boehringer Ingelheim Pharmaceuticals, Inc. for time and effort involved in participating in the discussion and reviewing the transcript for accuracy of content and readability prior to publication. The participants retained full control of the discussion and the resulting content of this article. The content was not reviewed or changed by Boehringer Ingelheim Pharmaceuticals, Inc. in any way.

In July 2008 a panel was convened to discuss the role of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in the treatment of hypertension and the management of cardiovascular risk. The moderator for the panel was Charon A. Pierson, PhD, RN, MS, GNP,BC, FAANP, the editor-in-chief of the Journal of the American Academy of Nurse Practitioners and Director of the Center for Aging at the University of Texas El Paso. Panel members were Mary Ellen Roberts, RN, APNC, MSN, FAANP, Practice Manager and the Nurse Practitioner in Clinical and Invasive Cardiology for a large private practice in Belleville, New Jersey, and Benjamin J. Epstein, PharmD, BCPS, Assistant Professor of Pharmacy and Medicine in the Colleges of Pharmacy and Medicine at the University of Florida in Gainesville, Florida.

PIERSON: Thank you for being with us today. We’re going to discuss the role of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors in hypertension management. Briefly we plan to review the importance of aggressive control of hypertension to reduce cardiovascular risk with a focus on the role of nurse practitioners. Second, we’ll review key concepts in understanding the pharmacology of ACE inhibitors and ARBs, particularly what these drugs offer in relation to aggressive control of hypertension and cardiovascular risk. Third, we want to discuss the ONTARGET results and their contribution to current perspectives on managing hypertension and cardiovascular risk and two key issues we want to focus on here are tolerability and adherence. And finally, we’ll discuss the management of hypertension and cardiovascular risk over various populations and settings.

I’m really glad to have both a nurse practitioner and a doctor of pharmacy on the panel with us today. It’s really important for us as nurse practitioners to be able to consult with our colleagues in pharmacy because the management of hypertension and cardiovascular risk is becoming so complex, and the therapeutic choices will only increase in the future.

I’d like to start by mentioning a recent study released in the Annals of Internal Medicine (Pletcher et al., 2008). I thought the findings were fascinating and they really speak to the problem that we’re going to have in relation to managing hypertension and cardiovascular risk in the future. This was a study of 3,560 participants, ages 18 to 30 when the study began. They were all prehypertensive, that is, they were in that prehypertension stage according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 guidelines; Chobanian et al., 2003) where pharmacologic treatment is not recommended. Their blood pressures were below 140/90, but above the normal of 120/80.

The findings I thought were so alarming were that even those low level elevations of blood pressure resulted in serious atherosclerosis and calcium deposits in coronary arteries in later life. This really speaks to the fact that we need to be aggressively managing hypertension and reinforces what the JNC 7 guidelines address: we have a significant way to go in managing hypertensive patients in order to get them to goal. Mary Ellen, in your practice, what has been your experience with younger patients in the prehypertensive states and how are you treating these patients?

ROBERTS: What we’ve done, particularly with patients that are prehypertensive, is treated them first with lifestyle changes. If their body mass index (BMI) is above 25, we start treating them with weight management, exercise guidelines, and get them out there moving. We tell patients to exercise at least a half an hour most days of the week. We try and get them to exercise and then we work on diet as well within the context of weight management. Then if they come back and their blood pressure is still at that prehypertensive stage, we’ll start them on pharmacological therapy. We may start off with a simple diuretic, but what we have found is that most patients, in addition to ongoing lifestyle changes, will need combination drug therapy at some point.

PIERSON: So you’re treating the prehypertensive patients when they have these high risk factors and they’re not responding to lifestyle changes?

ROBERTS: Right. Even in the younger population, the patients that are 35 years old who have prehypertension, they don’t want to start on medications they will have to take for the rest of their lives. So if we can get them to make lifestyle changes, which are going to be part of the treatment regimen anyway, we may be able to delay pharmacological therapy. If we say “you have high blood pressure and you need to take this pill,” they refuse it, and my experience has been that they’ve been non-compliant with medications if you give them no other options. Even if you start them on medications right away, you have to do the lifestyle changes as well, to get their blood pressures down.

EPSTEIN: Charon, I’m glad that you pointed out the CARDIA study (Pletcher et al., 2008) as it is an important prospective cohort study that expands our current understanding of the relationship between blood pressure in the prehypertensive range and target organ damage. CARDIA demonstrated that prehypertension during young adulthood increases the likelihood of coronary atherosclerosis later in life. However, the notion that low normal blood pressures are associated with harm is not novel. We have data from a meta-analysis that examined 1 million patients enrolled in 61 prospective studies (Lewington et al., 2002), which showed that risk begins to increase when blood pressures eclipse 115/75 mmHg. In fact, each 20/10 mmHg increase in blood pressure beyond this threshold doubles the risk of mortality from ischemic heart disease and other vascular causes. The data from this meta-analysis and the CARDIA study are compelling, collectively suggesting that blood pressure targets should be much lower than what current guidelines advocate.

In my practice, we identify patients who have blood pressures above the normal range, defined by JNC 7 guidelines as less than 120/80 mmHg, and decide whether or not pharmacological therapy is warranted based on risk. For patients with compelling indications for the use of a specific antihypertensive class, such as type 2 diabetes, heart failure, or renal disease, we select agents with proven efficacy in that setting.

For example, a patient with diabetes may be treated optimally with an ARB or an ACE inhibitor. A patient with angina might be treated with a non-dihydropyridine calcium channel blocker such as diltiazem or verapamil or a beta blocker. In the absence of compelling indications, we perform a global risk assessment, because our goal ultimately is not to lower blood pressure, but, instead, to prevent cardiovascular events. If we deem that the patient’s risk for cardiovascular disease, based on a Framingham risk score, warrants intervention, then we feel confident that lower blood pressure will translate into clinical benefits provided that therapy is tolerated.

So in patients such as you’ve described, we estimate the patient’s cardiovascular risk with a tool such as the Framingham Risk Score as is recommended by the National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health (2001) Adult Treatment Panel 3 (ATP 3) guidelines for patients with dyslipidemia. If the overall global risk for cardiovascular events is sufficiently high, then we’ll implement drug therapy to lower blood pressure. When selecting drug therapy we first identify compelling indications for a specific class of agents as outlined by the JNC 7 guidelines. Subsequently, we match drug therapy to the patient’s risk and comorbidities.

PIERSON: In other words, we need to go lower than the JNC 7 guidelines state. The guidelines call below 120/80 normal blood pressure, but you’re saying you prefer to have blood pressure below 115/75 according to the meta-analysis data that you’re looking at.

EPSTEIN: That is what the data suggest and fortunately we have accumulated considerably more information since the JNC 7 guidelines were published 5 years ago. Based on several contemporary intervention trials and the epidemiological data discussed earlier, I suspect that future guidelines will shift from an arbitrary blood pressure goal paradigm to a global risk assessment approach. The new paradigm will be one in which patients undergo risk assessment and if their cardiovascular risk is sufficiently high, drug therapy will be recommended regardless of blood pressure.

Some more recent guidelines from the American Heart Association and American College of Cardiology already recommend lower targets, suggesting that blood pressure should be less than 130/80 mmHg in patients with coronary disease and less than 120/80 mmHg in patients with heart failure.

PIERSON: You make a good point, that these guidelines are old. They have been revised several times, but they do get out of date quickly. As nurse practitioners we need to be looking for the best and most current evidence upon which to base our practice decision.

ROBERTS: One of the things that nurse practitioners do well, particularly in the clinical setting, is assess the whole patient. In addition to a global risk assessment, we have to look at what the patient’s going to tolerate and how they’re best going to accept treatment first before we institute any kind of therapy. If you say to some patients, “Okay, I’m going to give you this medicine,” they’ll be fine with that. Other patients are just going to refuse and be non-compliant. So we look at patients as a whole, and assess what they can accept at this point in their lives, particularly younger patients who just don’t want to be on medicine. We need to form partnerships with patients to accomplish these goals.

PIERSON: Good points. Well, that brings us to the next issue: when we’re talking about introducing medications into this mix, starting with a simple thiazide diuretic, which is certainly recommended in JNC 7. Thiazide diuretics may be indicated in some patients; they do get results and the therapy is inexpensive, but you’ve got to do the lifestyle interventions at the same time, otherwise treatment is not going to be effective. Let’s talk a bit more about some of the other medications we now have available.

EPSTEIN: Let me first underscore the importance of the renin angiotensin aldosterone system (RAAS) in the pathogenesis of cardiovascular disease. We know that in the RAAS, angiotensin II (AT2) is the system’s major effector peptide. Not only does AT2 increase blood pressure due to vasoconstriction but it also catalyzes effects that go beyond blood pressure. It is a potent vasoconstrictor and is pro-inflammatory, pro-fibrotic, pro-atherosclerotic, and causes vascular endothelial dysfunction. These actions encourage the progression of target organ damage and ultimately cardiovascular events in a way that we can’t necessarily appreciate in the clinic with a blood pressure cuff and stethoscope.

There are numerous studies demonstrating that inhibiting the deleterious effects of the RAAS results in beneficial effects that cannot be completely explained by the change in blood pressure. A classic example is the HOPE trial (Yusuf et al., 2000) in which the ACE inhibitor ramipril decreased the risk of cardiovascular death, myocardial infarction (MI), and stroke. Ramipril’s benefit was not entirely explained by the small reduction in systolic and diastolic blood pressure measured in the office. Both ACE inhibitors and ARBs are very effective at decreasing proteinuria in patients with diabetic and non-diabetic nephropathy. They are also an integral component of heart failure pharmacotherapy. The benefit in these populations is attributable to dimunition of the RAAS and not solely hemodynamic changes.

PIERSON: The drugs we’re currently using to block the RAAS are the ACE inhibitors and the ARBS – are they equivalent?

EPSTEIN: While these agents are often considered interchangeable, with clinicians commonly referring to the ARBs as “an ACE inhibitor without the cough,” that couldn’t be further from the truth. These drugs do work on the same axis, but they function very differently pharmacologically. The ACE inhibitors block the conversion of angiotensin I (AT1) to AT2. In doing so, they decrease the ability of AT2 to activate the AT1 and AT2 receptors. Additionally, ACE inhibitors decrease the degradation of bradykinin, and in doing so, they potentiate the effects of bradykinin. Augmentation of bradykinin levels can be considered a double-edged sword. On the one hand, bradykinin elicits beneficial responses such as vasodilation, antiplatelet actions, increased nitric oxide, ischemic preconditioning, and several other potentially favorable actions. On the other hand, it is also responsible for the increased risk of cough and angioedema in ACE inhibitor-treated patients.

In contrast to ACE inhibitors, ARBs selectively block the AT1 receptor. They directly decrease the ability of the AT1 receptor to promote inflammation, vasoconstriction, atherosclerosis, and several other nefarious effects. Both ACE inhibitors and ARBs elicit a compensatory rise in plasma renin concentrations. So patients treated with an ACE inhibitor or an ARB experience a rise in their plasma renin concentration which is due to increased synthesis and release of renin and prorenin from the juxtaglomerular apparatus and distal convoluted tubule in the kidney. The rising renin level ultimately drives increased production of AT1 from angiotensinogen. During ACE inhibitor therapy, AT1 can overcome ACE inhibition and be converted to AT2 through pathways that are independent from the ACE enzyme. We refer to this as either “ACE escape” or “AT2 reactivation.” Because of this escape phenomenon, ACE inhibitors do not completely block the RAAS. Consequently, increasing concentrations of AT2 during ACE inhibition can ultimately stimulate the AT1 and the AT2 receptor. In fact, AT2 levels have been shown to return to baseline levels within 6 months after initiation of ACE inhibitor therapy.

PIERSON: How do the ARBs differ in their mechanism of action?

EPSTEIN: In the case of ARBs, the reactive rise in renin, AT1, and AT2 concentrations are less worrisome since they are unable to stimulate the AT1 receptor, which ARBs selectively antagonize. Instead, circulating AT2 activates the unopposed AT2 receptor. The AT2 receptor promotes beneficial effects like vasodilation, anti-inflammatory effects, improved endothelial function, and more. In essence, the AT2 receptor counterbalances the AT1 receptor.

The major differences between ACE inhibitors and ARBs are that ARBS more completely block the harmful effects of AT2 over time while the ACE inhibitors increase bradykinin levels. Pharmacologically, it’s very clear that these drugs have a variety of differences that actually make them more different than they are alike, and so we really have to refer to randomized controlled trials and guidelines in order to determine whether or not these drugs can be used interchangeably.

PIERSON: So when we see these guidelines that say you can use any of these drugs, ACE inhibitors, ARBs, beta blockers, or calcium channel blockers, we need to stratify cardiovascular risk much more carefully in order to have a more appropriate understanding of the therapy that would help the patient the most?

EPSTEIN: Yes. The idea is to apply therapies in an evidence-based fashion and to select agents that not only lower blood pressure but also confer benefits beyond blood pressure lowering. This is the reason that the JNC 7 guidelines contain a “compelling indications” table. When a patient requires blood pressure lowering, you really need to consider their comorbidities in an effort to select the right antihypertensive drug. For a patient that has chronic heart failure and elevated blood pressure, the agents that you should be favoring are those that are recommended by the JNC 7 guidelines, which include either an ACE inhibitor or an ARB, a beta blocker, or a diuretic. These agents confer additional benefits in patients with hypertension and heart failure and the recommendations are evidence based. ACE inhibitors and ARBs, for example blunt neurohormones such as angiotensin II and norepinephrine that play an integral role in the pathogenesis of both hypertension and heart failure. They decrease preload and afterload which in essence unloads the left ventricle and makes it a more efficient pump. These effects cannot necessarily be appreciated in the clinic based on a blood pressure value.

So you’re right in suggesting that we need to look at the whole patient when selecting an antihypertensive drug. We can’t necessarily just choose from any of the agents because they work through pharmacologically distinct mechanisms and they have a number of important clinical differences.

PIERSON: The compelling indications table in JNC 7 is really very helpful for selecting appropriate therapy. Have things now changed as far as those compelling indications and the recommended drugs for those conditions or are we still waiting on more data?

EPSTEIN: Those compelling indications are largely unchanged. The one major difference is that ARBs are now more thoroughly studied. These agents have now been benchmarked against ACE inhibitors in most high risk populations.

For instance, the JNC 7 compelling indications table could be updated to reflect that there are convincing data with the ARBs in patients post-MI. In the post-MI setting, data from the VALIANT (Pfeffer et al., 2003) trial demonstrated that valsartan is equally as effective as the ACE inhibitor captopril given at a proven dose in the post-MI setting. We didn’t have these data when the JNC 7 guidelines were prepared. ARBs can now be considered as an alternative to ACE inhibitors in this setting.

We’ve also accumulated a considerable experience with ARBs in patients with a history of stroke. ARBs appear very effective for the secondary prevention of stroke. Studies such as ACCESS (Schrader et al., 1998) and MOSES (Schrader et al., 2005) support the use of ARBs for secondary stroke prevention and I think the compelling indications table could be updated to reflect these data. An ongoing trial called PROFESS (Diener et al., 2007) is examining the ARB telmisartan in a large population of patients with a history of recent stroke. This experience will help to further elucidate whether ARBs exhibit unique protection after stroke.

PIERSON: When you look at table 3 in JNC 7, you do not see the indication for ARBs in post-MI and recurrent stroke prevention. So we’re going to see that change in the newer guidelines whenever they are released. In the interim, should nurse practitioners be following other more current guidelines when they’re considering some of these populations?

ROBERTS: Absolutely, and it changes all the time. With the release of some of the newer agents that have come out recently, that also changes the mix a little bit as well. Hypertension management is one of those arenas that is constantly changing and we really do have to keep up with it. What’s nice about JNC 7 is that it does give you a very nice baseline and, although the guidelines need to be revised, there is good basic information here that everybody needs to know that will get you started.

PIERSON: I agree and I certainly see the value of getting clinicians to follow guidelines and to look at the evidence out there. In a busy practice, you may not have time to do a nice P-I-C-O question to explore the data on a specific population (P), intervention (I), control (C), or outcome (O) to find the best therapy for a given patient. Evidence-based practice guidelines, such as the JNC 7 or ATP 3, have synthesized the available data for us so we can feel fairly confident in treating the majority of our patients. It’s only in kind of extraordinary situations where you need to go to something different.

This brings us to the next topic: the ONTARGET study and what it has contributed to current perspectives on managing hypertension and cardiovascular risk (ONTARGET Investigators, 2008).

ROBERTS: What I see the ONTARGET study doing is focusing on cardiovascular risk factors and bringing them to the forefront so that they’re in everybody’s mind. You can’t just go by the blood pressure in and of itself. We have to get the word out to nurse practitioners about ONTARGET and what ONTARGET has done for the treatment of hypertension.

EPSTEIN: This study was designed in a very similar fashion to the HOPE trial, which demonstrated that the ACE inhibitor ramipril decreases cardiovascular death, MI, and stroke in patients that either have established vascular disease or type 2 diabetes and concomitant target organ damage. Before the results of ONTARGET we knew that ACE inhibitors reduce major cardiovascular end points by 15% – 25% in patients with hypertension, heart failure, post-MI , and diabetes but the data were less convincing for ARBs, especially in the setting of hypertension without heart disease, though many clinicians accepted ARBs as reasonable substitutes for ACE inhibitors.

ONTARGET was a prospective, randomized, double-blind trial that compared the proven ACE inhibitor ramipril with the long-acting ARB telmisartan and their combination in 25,620 high risk patients. At the end of the study, the Kaplan-Meier curves for the primary end point of cardiovascular death, MI, stroke, and hospitalizations for heart failure were nearly super-imposable. There was absolutely no difference between the ACE inhibitor and the ARB in this study. For me, these data confirm that ARBs are similarly effective compared with ACE inhibitors in patients similar to those enrolled in the ONTARGET trial, namely patients with a history of cardiovascular disease or diabetes and target organ damage. These 2 classes of agents confer similar levels of blood pressure lowering and cardiovascular protection in high risk patients. This is very salient for patients who don’t tolerate an ACE inhibitor, due to cough or rash in which case an ARB is considered the preferred agent. We now have convincing data from this large, well conducted clinical trial indicating that ARBs can be used in place of an ACE inhibitor comfortably, conferring similar outcomes in patients with hypertension. This information was not available prior to ONTARGET.

Another major finding from the ONTARGET trial was the fact that combining an ACE inhibitor and an ARB in this high risk population was no more effective than using the ACE inhibitor alone. This was counter-intuitive based on the pharmacology of ACE inhibitors and ARBs. I mentioned that these drugs work through very unique mechanisms of action even though they affect the same axis. It was theorized that by combining these drugs, greater RAAS blockade could be achieved, and correspondingly greater cardiovascular protection would be secured. Unfortunately that was not the case. Combining ramipril with telmisartan did not further decrease any of the primary or secondary end points. Instead, combination therapy was associated with an increased risk for adverse events, mainly hypotension, renal dysfunction, and hyperkalemia. Combining an ACE inhibitor with an ARB is still justified in select patients with chronic heart failure and nephropathy. In these scenarios, combination RAAS blockade has been proven to decrease the progression of cardiovascular morbidity and mortality in patients with symptomatic heart failure, and the progression of renal disease in patients with nephropathy.

In general, however, I no longer recommend routinely combining an ACE inhibitor with an ARB in patients with hypertension. Instead, I recommend maximizing the dose of an ACE inhibitor or an ARB and using additional, complementary agents as needed based on the clinical circumstances and evidence.

PIERSON: We tend not to be aggressive enough in maximizing dosages in treating some of these patients. I know the guidelines say that in certain categories of patients like stage 2 hypertension, you need to start with 2 drugs, that 1 drug is really not going to cut it. We need to start out aggressively and titrate these patients up to a level that they actually reach their goal blood pressure levels.

ROBERTS: I’ve seen clinicians I work with struggle with this issue. Patients are put on a medication, they come back for a recheck, their blood pressure isn’t where it should be, so the clinician tries another drug instead of increasing the dose of that first medication to make sure it’s an optimal dose. We really do need to maximize the dosages in these patients before we go on to something else.

EPSTEIN: This concept is currently being resonated in the literature (Basile, 2007) and the term that’s usually associated with the idea is “therapeutic inertia,” the notion that patients are started on a single antihypertensive drug, often at a suboptimal dose, and they tend to languish at low doses and high blood pressures. Unfortunately, medications are not advanced in a timely fashion and combination therapy is not started often enough up front. One of the pieces of data that I’ve found most compelling around the importance of prompt blood pressure control is a substudy from the VALUE trial (Weber et al., 2004; Julius et al., 2004). Dr. Weber and colleagues divided patients treated with either an ARB or a calcium channel blocker into groups who had immediately responded to their therapy or did not immediately respond. An immediate response was defined as a 10 mmHg or larger drop in systolic blood pressure at week 4. Patients who did not respond by week 4 had a 12% increase in cardiac events, a 17% increase in stroke, and a 10% increase in total mortality 5 years down the road! These data, as well as data from the Syst-EUR study (Fagard & Staessen, 1999), suggest that prompt blood pressure control forecasts reduced vascular risk into the future. Ideally, we need to treat patients earlier and more aggressively. This necessitates utilization of rationally selected combination therapy as step one in the treatment algorithm for many patients.

ROBERTS: We also have to remember with regard to risk factors that certain comorbidities such as diabetes could be considered in the same risk pool as having had a cardiovascular event in some of these patients.

EPSTEIN: Exactly. The ADVANCE trial (Patel et al. 2007), for example, enrolled patients with type 2 diabetes and randomized them regardless of their blood pressure to the combination of an ACE inhibitor and a diuretic or placebo. Patients did not have to be hypertensive to participate in ADVANCE. At the end of this trial, patients that were randomized to the ACE inhibitor and diuretic were far less likely to experience a cardiovascular event, regardless of their baseline blood pressures. One of the main reasons for this discussion today is to de-emphasize the importance of arbitrary blood pressure goals and instead shift the focus to overall risk by stressing the importance of identifying patients at high risk and then selecting therapies that are most likely to confer optimal vascular protection.

ROBERTS: One of the earliest and most important studies to address that point was the HOPE trial. The HOPE trial demonstrated that an ACE inhibitor such as ramipril is beneficial not only to patients who have left ventricular (LV) systolic dysfunction or heart failure, but there was a reduction of risk for future cardiac events even in patients without evidence of LV systolic dysfunction or heart failure. Before the HOPE trial we had anecdotal evidence that ACE inhibitors might reduce cardiovascular events in high risk patients, but the HOPE trial gave us some solid evidence that reducing blood pressure alone should not be the major clinical objective.

PIERSON: So how does that impact the adherence factor in medication? I mean hypertension has been one of those conditions where people don’t feel ill yet they have to take a medication every day for the rest of their lives. Patients don’t like that idea, and it costs money. How do you deal with that in practice, Mary Ellen?

ROBERTS: We gently let our patients know that this is going to be a lifelong problem. We tell them, “You now have been diagnosed with hypertension and you have several cardiovascular risks.” We go over the risks that they have because most patients don’t know that diabetes, smoking, or obesity are risk factors; they don’t realize that lifestyle choices are affecting their cardiovascular status. We do a lot of patient education to teach them that these are the things that have contributed to their condition. Gradually we will tell them, often not on the first visit, that this is going to be a lifelong problem we’re going to have to watch. This is going to be something that will require medication for the rest of their lives. Of course there are patients who, as soon as their blood pressure normalizes, will stop the medication. Then they come back in and they‘re in crisis again. Psychologically, it is very difficult for patients to grasp hold of the idea that they’re going to be on a medication for the rest of their lives, that cardiovascular disease is a lifelong problem. In order to decrease cardiovascular events, patients have to be compliant with their medication.

The other problem that patients have, particularly now, is cost. We have to look at the cost of some of these medications as well because patients simply can’t afford them.

PIERSON: In addition, tolerability affects a patient’s willingness to comply with taking the medication. Particularly what I always saw as a big problem in the elderly was the cough associated with the ACE inhibitors. As soon as cough starts in an older person in a long-term care facility, you have the potential for a very extensive work up for possible pneumonia, or other really life-threatening conditions that occur. So tolerability and adherence are two big issues related to successful management of hypertension and cardiovascular risk in patients.

EPSTEIN: As you allude, tolerability is a critical consideration in the management of hypertension especially when therapy with multiple agents is considered. Agents that cause fatigue, depression, sexual dysfunction, cough, nasal congestion, and pedal edema will affect adherence. This effect is heightened for an asymptomatic disease like hypertension. A recent network meta-analysis (Elliott & Meyer, 2007) examined the discontinuation rate of several antihypertensive medications. Older agents, such as beta blockers and diuretics are much more likely to be discontinued by patients. On the other hand, ARBs, a class of medications with placebo-like tolerability, are associated with the lowest discontinuation rate. While ACE inhibitors are better tolerated than older agents, cough tends to promote a higher rate of discontinuation compared with ARBs. Improved tolerability generally improves adherance, leading to improved blood pressure control.

So we need to consider early on in the course of therapy whether the agents that we recommend will bring about sufficient blood pressure lowering. As part of this process, tolerability, efficacy, and whether a single agent is sufficient must be entertained. The ARBs are one of the only classes of drugs that have been shown to increase quality of life in patients with hypertension. Typically you give a patient with hypertension, an asymptomatic disease, a drug that causes them to experience side effects and their quality of life goes down. When you treat patients with hypertension with a drug that has placebo-like side effects such as an ARB, they actually do feel better when you lower their blood pressure and that is a critical consideration to successfully treating patients with hypertension.

ROBERTS: I’ve found in my practice that many patients didn’t realize how badly they actually felt until they get on an ARB and then after a couple of weeks they’re like, “Wow, I didn’t realize that I felt as bad as I did. I thought that was the way I was supposed to feel.” They’re much better and their quality of life is definitely improved.

PIERSON: One other issue related to tolerability in the elderly: I see people who are active seniors in the community and they’re out exercising and they’re volunteering and they’re doing all kinds of things, and they’re really unhappy with diuretic therapy with issues of bladder control. While diuretics are not expensive necessarily, and they may be well tolerated other than urgency and frequency of urination, active seniors don’t have time or tolerance for that in their lifestyle and they will stop taking it.

EPSTEIN: Conventional beta blockers have to be put in that category as well because when you talk about the elderly, you’re talking about a group by and large that already has a reduced cardiac output. When you give that patient a beta blocker, in the absence of LV dysfunction, it causes a further reduction in cardiac output and they’re actually going to feel worse and they’re going to have a reduction in their ability to exercise. Both beta blockers and diuretics also have diabetogenic effects, they can contribute to dyslipidemia, and given the tendency of these risk factors to cluster, these are not desirable features.

ROBERTS: Patients don’t realize, they come in and they complain, “I’m tired all the time, I have this fatigue, I can’t get up, I can’t do anything, you know, what is wrong?” They don’t realize that this could be because of hypertensive symptoms or the medication they’re on. Then you put them on an ACE inhibitor or you put them on an ARB and all of a sudden the fatigue goes away because they’ve been treated properly.

PIERSON: Which goes back to the quality of life issue and the ARBs do seem to have the data to support the improvement in quality of life.

EPSTEIN: This has not been reported in ONTARGET, but fewer patients discontinued telmisartan than ramipril or the combination, which was largely driven by a decreased risk for cough.

PIERSON: They do have a table in ONTARGET about the reasons for discontinuation of the medication, and the hypotensive symptoms and the cough were certainly the most significant. There were others that actually may be even more important like the angioedema, which is a very important consideration. It may not be as frequent but it’s certainly potentially life-threatening in some patients.

EPSTEIN: ARBs clearly cause angioedema at a rate that’s much lower than ACE inhibitors. A question that oftentimes comes up is whether or not an ARB can be used in a patient with a history of ACE inhibitor-induced angioedema. Only limited data are available with which to answer this question. The best experience actually comes from a trial called CHARM-Alternative (Granger et al., 2003) which enrolled patients with New York Heart Association (NYHA) class 2 through 4 heart failure who did not tolerate ACE inhibitors. Most patients with ACE inhibitor intolerance reported a history of cough, but 39 of the 2000 patients had documented angioedema. When those 39 were given an ARB, 36 of them completed the 2 year study. So we have some data that suggests you can use an ARB in patients with a history of ACE inhibitor-induced angioedema but there may be a small risk for cross-reactivity. If an ARB is used in this setting it should be done so cautiously with close follow-up and documentation and the patient must have a compelling indication for RAAS blockade.

PIERSON: Sometimes myths get started, such as “you can’t use X drug because it cross-reacts with Y drug,” and this is perpetuated in the minds of clinicians so it’s nice to know that we do have data to suggest that ARBs do not act the same way in patients who are intolerant to ACE inhibitors. We should be cognizant of that data as we try some of these medication regimens.

We haven’t really yet talked about managing hypertension in the primary vs. acute care arenas. Mary Ellen, you function in both settings. Can you kind of give us an overview from your experience in primary care vs. acute care in the management of hypertension with respect to the ACE inhibitors and the ARBs?

ROBERTS: Well, we have found in the acute care setting that most patients with hypertension who are hospitalized for a blood pressure of 190/100 mmHg, for example, we will start them right away on either an ACE inhibitor or an ARB. Generally, either the ACE inhibitor or the ARB, depending on the patient, will really aggressively bring that blood pressure down in the hospital, and then the patient goes home on the ACE inhibitor or the ARB because these drugs are well tolerated. I find these drugs work quickly to get the blood pressure at least to an acceptable point, maybe not to goal, but at least to an acceptable point. Of course, when they come out of the hospital these patients need aggressive follow-up. The problem is, as everybody knows these days, patients aren’t in the hospital for long periods of time. They’re admitted, you take care of their immediate need, and they’re out. Most of these acute care patients are primarily treated on an outpatient basis. If they’re in for two days, that’s a long time. Hospitalization is required just to get them out of that hypertensive crisis stage.

Then they come in to the office and that’s where we start the patient education, that’s where we really start again increasing doses as we see the need for better control. If they were hospitalized for a hypertensive crisis, we’ve given some intravenous medications that will also help to get their blood pressures down as well. Basically, a lot of what we do in the acute care setting is to get them prepared for the outpatient setting.

PIERSON: That’s a good way to put it –whatever you start in the hospital you want to maintain in the outpatient setting.

EPSTEIN: Most importantly, the patients you’re discussing are not going to reach goal on a single drug. These patients are going to need two to four antihypertensive drugs to get to goal. The JNC 7 guidelines that are out there now advocate for combination therapy used initially in both patients with stage 1 and stage 2 hypertension. Essentially any patient unlikely to get to goal on a single drug should be started on two, given as a fixed dose combination to improve adherence, from day one. When you think about all the ways that you could combine two drugs, the ACE inhibitors and the ARBs emerge as a cornerstone. I fully agree that you start these drugs early on in the management of these patients because this needs to be their foundation. An ACE inhibitor or an ARB should generally be combined with either a calcium channel blocker or a diuretic. This combination is attractive for a couple of reasons. First, pharmacologically, these agents work on counter-regulatory systems, making blood pressure control superior and more consistent. The diuretic or calcium channel blocker activates the RAAS, which means that if the second drug is a RAAS antagonist, the combinations works in complementary fashion. This is one reason why our armamentarium is replete with combinations that combine ARBs and diuretics, and now ARBs and dihydropyridine calcium channel blockers.

Second, as we’ve already discussed, we know that the ARB or the ACE inhibitor will confer benefit that goes beyond simply lowering blood pressure. Third, by using an ACE inhibitor or an ARB as part of the combination with a calcium channel blocker or a diuretic, you’re actually able to decrease the likelihood that the patient will experience side effects.

I’ll give you two examples. Diuretics promote metabolic abnormalities, namely hypokalemia, hypomagnesemia, and hyponatremia. Such aberrations can lead to type 2 diabetes and dyslipidemia. Calcium channel blockers frequently cause pedal edema. Using either an ACE inhibitor or an ARB alongside a diuretic or calcium channel blocker mitigates the risk of peripheral edema or electrolyte abnormalities and new onset diabetes and dyslipidemia. Thus, using a RAAS blocker early in the treatment algorithm as part of combination therapy affords several advantages

PIERSON: This leads to the discussion about specific populations and, in particular, specific ethnic groups. We have all read and heard that ACE inhibitors don’t work as well in the black population, and I think that we now have sufficient evidence to suggest otherwise.

ROBERTS: I work very close to an inner city and I see a lot of African-Americans in our practice. In the population that I work with, we actually use a lot of ACE inhibitors and they absolutely do work. We have to remember, however, that in this population ACE inhibitors or ARBs must be combined with another drug like a diuretic or a calcium channel blocker. This combination therapy is very effective regardless of race, age, or gender.

EPSTEIN: One of the reasons that this fallacy was promulgated was based on the observation that African-American patients have low renin hypertension. Correspondingly, they theoretically respond less consistently to drugs that block the RAAS. It has been shown that African Americans in general don’t respond quite as well with respect to blood pressure change with an ACE inhibitor or an ARB than say a diuretic or a calcium channel blocker. This is only true with regard to monotherapy as Mary Ellen pointed out. As soon as you begin to combine drugs, which most African-American patients will require, no longer do we see heterogeneity in response because the diuretic and the calcium channel blocker actually takes patients with low renin hypertension and converts them to high renin hypertension. In this setting, the ACE inhibitors and the ARBs lower blood pressure as well as other classes, irrespective of race.

The other important thing to keep in mind is that while African-Americans have a low plasma renin concentration, they often have very high levels of tissue renin activity, particularly renal renin activity, which means that they stand to benefit from RAAS blockade and these agents should not be withheld based on race.

ROBERTS: It’s also important to decrease risk for target organ damage in African Americans, a population at increased risk of adverse renal and cardiovascular outcomes. This can only be achieved with aggressive therapy as we’ve discussed here. Guidelines from the International Society on Hypertension in Blacks (Douglas et al., 2003), which have been endorsed by the Association of Black Cardiologists, recommend therapy using combinations of thiazide diuretics, beta blockers, dihydropyridine calcium channel blockers, ACE inhibitors, or ARBS.

EPSTEIN: The key message is that African Americans need RAAS blockade, which often requires combination therapy. Whether a calcium channel blocker or diuretic should be used in combination with a RAAS blocker was investigated in the ACCOMPLISH trial (Jamerson, 2008). ACCOMPLISH randomized high risk hypertensive patients, including African Americans, to an ACE inhibitor and a diuretic or an ACE inhibitor and a calcium channel blocker. Patients treated with the ACE inhibitor and calcium channel blocker fared better, including African-Americans, when compared with those on an ACE inhibitor and a diuretic. We don’t know why, because blood pressure was identical; the difference was only 0.7 mmHg. There was a 20% reduction in cardiovascular death, MI, and stroke in patients that were given the calcium channel blocker and the ACE inhibitor. Now whether that’s due to a more favorable metabolic profile of the calcium channel blocker or due to some other effect such as anti-atherosclerotic actions or increased nitric oxide bioactivity, we don’t yet know but the data may be practice-changing in that it suggests patients such as those enrolled in ACCOMPLISH fare better with a calcium channel blocker-based combination regimen than a diuretic-based strategy.

One of the key things I’ll be looking for is how various patient types respond to either of the combinations. We may find, for example, that patients at risk for heart failure respond better to the combination of an ACE inhibitor and a diuretic whereas patients that have type 2 diabetes respond better to the combination of an ACE inhibitor and a calcium channel blocker.

PIERSON: Are there any other populations that we need to focus on from your perspective? How about males vs. females? I know earlier on we didn’t have as many females involved in some of these studies.

ROBERTS: I don’t see a significant change in that. I personally don’t treat males or females any differently.

EPSTEIN: I agree with one caveat: pregnant women should not receive any form of RAAS blockade. Likewise, I’m very cautious in how I apply ACE inhibitors and ARBs, and now direct renin inhibitors as well, in females of reproductive age. These agents are associated with teratogenic effects and so if I do choose to use them in females of childbearing age, I typically ensure and verify effective methods of contraception.

PIERSON: Another population that we’re becoming aware of, particularly where I live on the border between Mexico and Texas, is the adolescent population with extreme obesity and documented hypertension in pediatric populations. Treatment options for hypertension in this age group must involve the entire family. This is a growing population, and there’s a lot of damage being done in young people as far as their arteries with just prehypertensive states. We also have adolescents who are being treated with medications for true hypertension.

ROBERTS: Hypertension is becoming more prevalent in adolescents and a lot of it is due to the amount of obesity that we see in this population now. I have seen that clinicians are more aggressive in putting young people on antihypertensive agents, particularly the ACE inhibitors and the ARBs, and they are looking at smaller doses that will be effective in these children. We also have to remember to discourage the use of anabolic steroids and we need to vigorously look at interventions such as weight loss and physical activity, because long term exercise may actually help lower blood pressure. Of course, we must look at other existing modifiable risk factors, such as smoking.

EPSTEIN: Drugs that block the RAAS in younger patients are very well tolerated and this is a population that has a lower threshold for dealing with side effects. They’re more likely to discontinue therapy if you prescribe agents that cause side effects, particularly calcium channel blockers in younger females because they are not very accepting of any level of pedal edema and beta blockers or diuretics in younger men because they cause erectile dysfunction. We need to use agents that are well tolerated and we also need to use agents that have a disease modifying effect. We’ve seen from studies like TROPHY (Julius et al., 2006) that drugs that block the RAAS may be able to modify the progression of vascular disease and may be able to change the trajectory of blood pressure over time. Also, diuretics and beta blockers, while they’re recommended first line for adults with hypertension in some guidelines, need to be applied more cautiously in younger patients because they can cause hyperglycemia and hyperlipidemia. These adverse effects in younger patients may be realized over decades if we treat these patients for substantial periods of time. Because ACE inhibitors and ARBs are metabolically neutral or beneficial, very well tolerated, and have disease modifying potential, they really make good sense even in the absence of randomized controlled trials for use in younger patient populations.

PIERSON: That’s a really good point because you’ve already got adolescent youth who are obese and now you’re adding a diuretic that has the potential to cause type 2 diabetes which they are already at great risk for because of their obesity. So it seems like ACE inhibitors and ARBs would be the logical choice.

EPSTEIN: ACE inhibitors are approved for use in adolescents; ARBs are approved to treat kids as young as six. The dose of ACE inhibitors and ARBs should be modified based upon age and weight.

ROBERTS: In addition to selecting the appropriate drug, we really must work with the patient and come up with a patient contract where both the clinician and the patient agree upon what the blood pressure goals are. It has to be patient-centered, otherwise they’re not going to reach goal because they’re not going to understand or comply with treatment. Self-monitoring of blood pressure is useful in some patients; in other patients it’s not because some patients get very obsessive with it. Non-adherence to therapy usually is caused by misunderstanding the condition and the treatment that we’re using or the patient denies the fact that they have an illness. Sometimes these patients don’t have any symptoms and they perceive themselves as healthy, so when we tell them they need medications, it’s the equivalent of telling them they’re ill.

We need to truly involve patients in this care plan and explain to them what adverse effects they may have from the medications so they are not surprised. The more we can educate patients and the more we can work with our patients as partners, the more likely they’re going to get to goal. The added benefit is they will be more likely to trust you and talk to you about various issues that are going to complicate their care, such as the cost of medications, their transportation problems, and the difficulty they have in scheduling appointments. Those problems are barriers that we need to overcome to achieve good outcomes in these patients.

PIERSON: We really do need to partner with patients in a number of conditions, not just hypertension. We see the same thing in treating hyperlipidemia, that patients are not getting to goal because they don’t understand the seriousness of the problem, they are not participating in a contract and establishing goals for themselves; and we clinicians are not as aggressive in treating some of these conditions as we should.

We’ve covered a lot today in this discussion and I’d like to thank our panelists again for helping us understand the role of ACE inhibitors and ARBs in practice. Just to summarize a few key points, the research clearly shows the need for aggressive therapy for hypertension using regimens that effectively control for and reduce cardiovascular risk. One way we can do this is by starting treatment early, maximizing dosages of medications, and using combination therapy that is based on the best and most current evidence from large, prospective, clinical trials and meta-analyses. And finally, we should feel comfortable treating hypertension with ACE inhibitors and ARBS in a variety of settings and populations based on the current evidence.

We’ll be looking forward to new evidence-based guidelines as they are released and we trust we’ll see more emphasis on cardiovascular risk assessment and risk reduction in the future.

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