Abstract
A panel was convened to discuss current combination therapy for hypertension. Alan H. Gradman, MD, of the Western Pennsylvania Hospital, Temple University School of Medicine (Clinical Campus), Pittsburgh, PA, moderated the discussion. Participants included Matthew R. Weir, MD, University of Maryland School of Medicine, Baltimore, MD, and George L. Bakris, MD, University of Chicago, Chicago, IL.
DR GRADMAN:
Combination therapy with diuretics + angiotensin‐converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB) or β‐blockers and ACE inhibitors combined with calcium channel blockers (CCBs) have been used for many years with good results. Recently, combinations of an ARB and a calcium antagonist have been studied. There is almost universal recognition that most people with hypertension require more than 1 medication to achieve their goal blood pressure (BP). ARBs and CCBs have been used in several clinical endpoint trials as monotherapy and in combination with other medications with good results. In this discussion, several experts discuss combination therapy in general and address issues that are specific to combinations of ARBs and CCBs.
George, if you look at the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, why do they emphasize that therapy with more than 1 medication should be a part of our management of hypertension?
DR BAKRIS:
We have recognized for a number of years, going back to the 1980s, that monotherapy simply does not achieve BP goals in many patients and that multiple agents are required for most patients, especially those with more severe hypertension or evidence of target organ involvement. It has also become clear that to achieve BP goals in a timely fashion, we often need to initiate therapy with 2 different medicines. In JNC 7, we reviewed the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD) as well as many others. In this trial, a combination of a renin‐angiotensin system (RAS) blocker with a CCB compared with traditional monotherapy doubled or almost tripled the control rates when combinations were used as initial therapy, compared with the dose‐titration method. [Note: The FDA has not specifically approved Lotrel for use in patients with diabetes or as a first step therapy.] The most sobering piece of news that came out of that trial was that even after adding a diuretic to traditional therapies, there were fewer people controlled at <140/90 mm Hg 1 month later. This provided good evidence to support the notion that initiating therapy with a combination rather than starting with monotherapy and increasing the dose was more effective strategy for achieving goal BP expeditiously, especially in persons with stage 2 hypertension.
DR GRADMAN:
Yes, I think the point that you make is important. We will return later to a discussion of using combinations as initial treatment. I think it is worth noting in this context that the need for combination therapy has been recognized since the 1980s. Furthermore, today's target BP, the goal levels recommended in JNC 7, are in many cases significantly lower than what was recommended 20 years ago and this has led to the need for multiple drugs in a much larger fraction of the hypertensive population. For example, target BP in patients with diabetes is now 130/80 mm Hg instead of 140/90 mm Hg, and some authorities also utilize these lower targets for patients with the metabolic syndrome. Diabetics, in particular, constitute an ever‐increasing proportion of the hypertensive population. Matt, why is it that an aggressive approach to combination therapy is so essential; why is it so difficult for clinicians to achieve goal BP in their patients either with monotherapy or even with 2‐ or 3‐drug therapy?
DR WEIR:
For me, the biggest change I've seen during the past 10 years has been the shift from targeting diastolic BP as the primary goal to focusing on systolic BP. Another thing that I think has been important is the recommendation to lower goal systolic BP from 140 mm Hg to <130 mm Hg if there is evidence of an estimated glomerular filtration rate (GFR) <60 mL/min or, as you mentioned earlier, diabetes. And the last thing that think has confounded our ability to get some people to goal BP is that today we're caring for more and more overweight hypertensives who have sedentary lifestyles and tend to consume a lot of salt. When you combine a focus on systolic BP, lower recommended BP goals, and more overweight people, you end up with fewer people who will respond to a single agent. This almost forces you into the use of 2 drugs or fixed‐dose combination therapy at the outset of treatment in many patients. There is still a reluctance on the part of many physicians who feel very uncomfortable starting with 2 drugs, even in people with systolic BP that is >20 mm Hg above goal. I believe that a major issue is that we start the treatment of high BP too late in its course to achieve goal BP with a single medication.
DR GRADMAN:
Matt, I think your point about systolic BP is important. For years, we paid little attention to systolic BP. When diastolic BP of <90 mm Hg was achieved in a patient receiving drug therapy, our tendency was to believe that he or she didn't need additional therapy, even if the systolic BP was still a little elevated. Another reason for the increased focus on systolic pressure relates to the aging of the population and the fact that systolic BP rises progressively with age, while diastolic pressure tends to decline after the age of 50. The result is that all of us who treat hypertension are taking care of an ever growing proportion of elderly patients with isolated systolic hypertension. With their high systolic BP, these patients' hypertension is often difficult to control with a single drug or sometimes even with 2 or 3 drugs. New approaches to therapy may be needed.
George, we now have a new combination of an ARB and a CCB for the treatment of hypertension. Are there any advantages to this combination? You mentioned some data regarding diuretic combinations. How do you see an ARB/CCB combination differing from an ACE/CCB or an ACE inhibitor/diuretic combination, for example?
DR BAKRIS:
We have very good data on diuretic combinations with ACEs and ARB inhibitors, and there is no question they are good BP‐lowering agents and certainly better than either agent alone. So that's a given. We now have data comparing diuretic‐based combinations with ACE inhibitor/CCB combinations in terms of new‐onset diabetes (NOD), and it's clear that at a similar level of BP control, you have fewer cases of NOD with an ACE inhibitor/CCB compared with an ARB/diuretic combination. So the metabolic risk appears to be reduced or eliminated when using a RAS blocker with a CCB.
Now the advantage of an ARB/CCB combination is that the number of adverse effects with ACE inhibitors (eg, angioedema, cough) is less and efficacy is similar. This seems like an optimal combination: the ARB has no dose‐dependent adverse effects and, at the same time, you have the efficacy of a CCB. The edema associated with a CCB is reduced when a CCB is used in combination with an ARB. So, from a tolerability standpoint this combination clearly appears to be superior and from an efficacy standpoint, it's just as good.
DR GRADMAN:
Matt, do you have anything to add to that? We are focused on the ARB/CCB combination compared with other combinations. I think we've all decided that combination therapy is a practical necessity. The question relates to these specific combinations and what advantages you see, if any.
DR WEIR:
I have had this conversation for a number of years about optimal treatment regimens. I believe RAS blockade should be the foundation upon which other therapies are used to assist in BP reduction. My feeling is based on the consistent evidence from outcomes trials that lower BP and blocking the RAS is associated with a reduced likelihood of progression of kidney, cardiovascular, and cerebrovascular disease.
Now the real question is: What's the best therapy to use with RAS‐modifying therapy? If you really want to get BP under control, it's either going to be a thiazide diuretic or a CCB. Obviously, these are both excellent choices for facilitating BP reduction. But the real question is whether one therapy will be better than the others for reducing cardiovascular outcomes. Unfortunately, we will not have an answer to that question for another few weeks until the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial is completed. In short, the ACCOMPLISH trial is a clinical trial in which all 11,000 patients receive the ACE inhibitor benazepril in a dose of 40 mg in addition to being randomized to receive either 5 to 10 mg of amlodipine or 12.5 to 25 mg of hydrochlorothiazide. Additional conventional non‐ARB/non‐ACE inhibitor therapies can be added to facilitate getting BP to either <140/90 or <130/80 mm Hg, depending on their cardiovascular comorbidity, much in line with the JNC 7 recommendations.
For now, without an outcome trial, I choose the accompanying therapy based on tolerability. In general, for women, prefer a thiazide simply because some women like the weight loss associated with diuretics, and think postmenopausal women will have the advantage of the thiazides facilitating some retention of calcium, particularly with regard to their bones. For men, however, I tend to add a CCB, in large part to avoid any complaints about decreased libido or issues related to gout, which are admittedly uncommon but still potential problems with a thiazide. Men tend to be less likely to complain about subtle changes associated with lower extremity edema, which may occur with the CCB.
That being said, metabolic issues which are associated with thiazide use may also be a concern, influencing whether one uses a thiazide or a CCB with an ACE inhibitor or an ARB.
DR BAKRIS:
I think if you look at data on the background of an ARB or an ACE inhibitor, in patients who are ‘metabolically challenged’ (those with impaired fasting glucose in the range of 100–120 mg/dL), a patient is not protected from NOD if 25 mg of hydrochlorothiazide is given. And even at 12.5 mg, you're going in the wrong direction. Data from the Study of Trandolapril/Verapamil‐SR and Insulin Resistance (STAR) showed that at 1 year using a RAS blocker/CCB combination prevented the development of NOD, whereas using an ARB/diuretic did not. There was a difference of 80% between these groups in NOD at 1 year. [Note: No antihypertensive agent or drug combination has been approved for prevention of new‐onset diabetes.] The study was extended for 6 months and everybody who was on the ARB/diuretic combination was switched to a CCB/ACE inhibitor combination; 50% actually regressed to nondiabetic status. Although we are not certain of the significance of NOD, this would appear to be a benefit of ACE inhibitor/CCB therapy. Only 21% of the patients whose BP was well controlled when they were switched to the ACE/CCB therapy lost BP control; that is to say that in >70% good BP control was maintained. This is important in that you're not sacrificing BP control and yet you're preserving metabolic balance in people at high risk.
Now, is this relevant in people who don't have metabolic risk? Well, we don't know, but it's probably not as relevant.
DR GRADMAN:
Well, given the numbers Matt referred to earlier (ie, the rising proportion of patients we all see who are overweight and have various components of the metabolic syndrome), I think this is a particularly important point and one that we're all concerned about. Let me ask one other question. We've talked about ARBs, CCBs, and diuretics in various combinations. Why are there no fixed‐drug combinations of CCBs and diuretics? Matt?
DR WEIR:
This is an issue I've been interested in for many years. The literature on this subject goes back 20 years. Many years ago, we were involved in some studies that looked at the utility of combining hydrochlorothiazide with the non‐dihydropyridine CCB diltiazem. In fact, it works quite well. Similarly, some studies were performed with indapamide and verapamil, revealing complementary antihypertensive effects. But interestingly, the studies with thiazide and dihydropyridine CCBs show only modest improvements in BP. This suggests to me that there may be slightly different mechanisms of action, as well as some overlap in the mechanisms of action by which thiazides and dihydropyridine CCBs lower BP.
DR GRADMAN:
Yes, I think that's true. CCBs and diuretics, when combined, produce less than additive BP reduction. This brings me to another important principle of combination therapy. When we devise combinations, we're not just looking to combine any old pair of drugs; we're looking to combine drugs that have complementary pharmacologic mechanisms of action and, hopefully, produce additive BP reduction. So, I think that's probably the reason these combinations have not been marketed, although we all use CCBs along with diuretics. I, for one, frequently give ARBs, CCBs, and diuretics together in a triple‐drug regimen. This more aggressive approach is required in a significant proportion of patients.
DR WEIR:
There are efforts to develop an amlodipine and hydrochlorothiazide or possibly chlorthalidone fixed‐dose combination. With this type of combination, however, one may not have the same opportunity of neutralizing some of the pedal edema responses due to the CCB with a thiazide, compared with an ACE inhibitor or an ARB.
DR GRADMAN:
That's an important observation and one that brings us to another important aspect of antihypertensive therapy in general and combination therapy in particular. That is the issue of the tolerability of drug therapy and the impact that drug tolerability has on quality of life and adherence in patients with hypertension. I want to discuss where these new combinations of ARBs and CCBs fit into the tolerability spectrum. Some of this was brought up earlier. I think, Matt, you mentioned that there might be a tolerability advantage to an ARB/CCB combination, which, unlike ACE inhibitor/CCB combinations, is associated with much lower frequency of ACE inhibitor‐related adverse effects such as cough and angioedema. What about peripheral edema? It is well known that this is, in fact, a dose‐limiting side effect of CCBs. Many people are not aware of the fact that you can get additional BP reduction by increasing the dose of amlodipine to >10 mg/d. The reason this is not done very often is that, at higher doses, the edema rates are so high that patients don't want to take their medication. George, how important are adverse effects in determining long‐term adherence to antihypertensive drug regimens?
DR BAKRIS:
Oh, I don't think there's any question. Depending on which survey you read or what analysis you've looked at, tolerability or adverse effects of medicine are consistently 1 of the top 2 reasons for nonadherence to medication regimens. So I would say they're vitally important and that cost and dosing schedules are also important and consistently relate to long‐term adherence. So I don't think you can overemphasize the tolerability of a medication. And ARBs certainly have the best tolerability of any of the BP‐lowering agents. Combining them with a CCB increases effect and preserves tolerability in most cases, because they manage edema better than diuretics. You don't have the cough; you don't have the angioedema incidence that you have with the ACE inhibitors. Not that it's nonexistent. The cough is, and the extent of angioedema is infinitesimally small compared with ACE inhibitors. I think these are important issues.
DR GRADMAN:
Yes, there is nothing more important than adherence. If patients don't take their medications, it doesn't matter how good the medications are, they are simply not going to control BP or prevent the long‐term complications associated with hypertension. We all know this, but it's easy to forget when you are dealing with patients one‐on‐one. I remember how we used to write prescriptions for large doses of methyldopa or β‐blockers and often treated patients with 100 mg/d of hydrochlorothiazide. We then wondered why people didn't take their medications as directed. It is now recognized that these therapeutic regimens had a major adverse effect on patients' quality of life. Today's medications are infinitely better tolerated than these drugs were, but there are still adverse effects. And edema, as I said before, is the dose‐limiting adverse effect for most CCBs. Getting a clear picture of the edema issue is challenging, however. In some cases, edema as reported in clinical trials seems to be somewhat different from the edema we observe when patients come to our offices. We know that if you look at different clinical trials, there are sometimes very differing edema rates reported, even with the same drug given at the same dose. So the question here is how do clinical trials help us or not in terms of understanding edema and how do we deal with it in clinical practice. Matt?
DR WEIR:
How to extrapolate the trial data to clinical practice is often difficult and I think that is the basis of the question that you're asking. The issues of pedal edema are subjective at best, and as review the literature, it is more commonly reported in women. We also know that it is affected by body mass index, season, time of measurement, ambient salt intake, and concomitant use of other drugs such as thiazolidinediones. There are many factors that can influence it and how patients report it. Consequently, what we see in our patients in the office may not be a reflection of what exists in the real world. During the summer, for example, nearly every patient taking ≥5 mg of amlodipine is going to have some measurable pedal edema by the end of the day, regardless of what they're being treated with as a cotherapy.
DR GRADMAN:
Why do you think they get more edema during the summer?
DR WEIR:
I think it's caused by the heat and by being on their feet, which facilitates capillary leak. But it is common, and so it is very difficult to quantitate. We did some studies here years ago using Archimedes' principle of water displacement to measure the volume of the lower extremity. We had patients step into a measured container of water where we could assess water displacement during leg immersion. This provides a more objective way to assess ambient leg volume. Even using this objective approach, we still had quite a bit of variability among patients when followed longitudinally. This suggests to me that there is a lot of inherent variability in measuring leg edema, depending on the temperature, time of day, ambient salt intake, and all the other factors that I previously mentioned. I think the bottom line is that each patient has their own threshold of tolerability for leg edema. Thus, one should individualize therapy accordingly.
DR GRADMAN:
You mentioned ambient salt intake. Normally, we think of edema resulting from CCB use as being due to a local vascular phenomenon that is not readily relieved by diuretics. Tell us more about salt intake and the edema associated with CCBs.
DR WEIR:
We can all agree, Alan, that CCBs are natriuretic drugs. It is very unusual to develop water retention with these drugs unless the patients have worsening systolic heart failure. This is rare. So, in reality, the pedal edema that is observed with CCB use is usually related to some form of capillary leak syndrome due to the potent arteriolar dilation associated with this drug class. With that being said, greater ambient sodium consumption will create even more vascular volume, which may render the patient even more susceptible to capillary leak with CCBs. I want to be fair and say this is pure conjecture on my part.
DR GRADMAN:
Another interesting finding that was reported in one of the combination studies recently presented at the American Society of Hypertension (ASH) meeting was that age was also a factor in the development of edema. Do either of you have any comments on the relationship between age and edema and why it might be that older people have more edema with CCBs, compared with younger individuals?
DR WEIR:
Were appropriate adjustments made for body mass index and other demographic factors?
DR GRADMAN:
I'm not certain.
DR BAKRIS:
Well you know, there would be one obvious reason edema is more common in older people, especially older women, and that has to do with venous capacitance and the presence of varicose veins and valvular abnormalities that occur with age, especially in people older than 70 years. I mean, if you look at the mechanism of edema, it's not sodium retention, it's vasodilation and basically a mismatch between greater vasodilation on the arterial circuit and reduced capacity to return the blood in the venous circuit, with gravity basically pooling the blood in the legs. Improvement with RAS blockers relates to increases in venous capacitance. But even RAS blockers used in older individuals may not totally resolve the edema, especially in persons with venous issues, either varicose veins or some type of valvular problems in the venous system, or patients with heart failure and pump dysfunction.
DR GRADMAN:
Definitely. The other question that I want to revisit is the idea of real‐world rates of edema vs results reported in clinical trials. We have all seen studies, several presented at the last ASH meeting, in which edema rates as high as 25% were reported. From my perspective, this seems a bit high. So, questions for the two of you are (1) Are such results related to the baseline edema status of the population studied? (2) What determines the baseline rate of edema in a population? and (3) Where are we starting from in patients receiving CCBs or other agents?
DR WEIR:
I think it depends on the body mass index. I can tell you that in my experience, if the body mass index is ≥30, there is almost universal evidence of pedal edema by the end of the day for my patients with afternoon appointments, regardless of therapy.
DR BAKRIS:
I would have to say the same thing. Keep in mind that in insulin‐resistant states, which are what Matt's describing, people have high insulin levels. It is well known that insulin increases proximal tubule sodium reabsorption and, if you actually measure the total body sodium level in these patients as Parving's group did many years ago, they are all going to have expanded volumes. So there is no reason for them not to have some edema.
Now, the sensitivity to that edema is quite a different issue. In terms of women being more sensitive than men because their shoes are sometimes tight, and how that actually translates into adherence to medications depends on the individual more than anything else. But, in general, women are going to be less tolerant to edema than men. But I don't think we really know the true incidence because it's not really been measured.
DR GRADMAN:
At times, sorting all of this out can be very confusing. We do know that some drugs cause a lot more edema than others. So in the Valsartan Antihypertensive Long‐Term Use Evaluation (VALUE), which compared valsartan‐ and amlodipine‐based therapies, there was clearly more edema with amlodipine (which causes edema) compared to ARBs (which do not). George, what happens to edema when you combine an ARB with a CCB?
DR BAKRIS:
It doesn't go away but I'd say it's reduced by at least 50% and maybe even as much as 70%. But you will still get edema in that setting; you simply won't get it to the same magnitude.
DR WEIR:
I agree completely. I believe that there's no question, but they certainly do not prevent it. In large part, many of these patients already have pedal edema due to the visceral adiposity that may interfere with normal venous and lymphatic return. Consequently, a CCB may make it worse by causing a capillary leak syndrome. Dietary salt intake can make it worse, even if a drug that improves venous capacitance (such as an ACE inhibitor or ARB) is given. An ACE inhibitor or ARB will not overcome the problem of salt in the diet or visceral adiposity interfering with venous and lymphatic return. I tell my patients that if they want to get rid of the edema, they have 2 choices: either lose weight or wear support stockings.
DR GRADMAN:
How do combinations of ARBs and CCBs compare with the combinations of ACE inhibitors and CCBs in terms of reducing edema incidence? In a paper presented a few years ago, there was about a 50% reduction in edema rates when an ACE inhibitor was added to a CCB. Do you think that same magnitude of reduction holds with the CCB/ARB combinations? George?
DR BAKRIS:
Yes. I think it would be very similar. I mean, it may be 45%, it may be 55%, but it's going to be very similar.
DR GRADMAN:
What did you think of the study that was presented at the ASH meeting in which a 25% edema rate was reported with one of the CCB/ARB combinations? This seems like a very high figure to me. Do either of you have any thoughts on this study?
DR WEIR:
I'm not familiar with the paper, but I will say this: I have reviewed literature on the effects of thiazides, ACE inhibitors, and ARBs in conjunction with amlodipine therapy. Although we have done contemporaneous head‐to‐head studies with ACE inhibitors vs thiazides, I think ACE inhibitors are better than thiazides in reducing pedal edema with use of a CCB. There have been no head‐to‐head studies between an ACE inhibitor and an ARB. The data from non‐contemporaneous trials reveal a somewhat similar effect with ARBs as with ACE inhibitors in terms of attenuating pedal edema complaints associated with the CCB amlodipine.
DR GRADMAN:
So, in your experience, complaints about edema are reduced by approximately the same magnitude even though a somewhat different result might be reported if one were to utilize some objective measure of edema?
DR WEIR:
I would say more or less.
DR BAKRIS:
I would agree. I think fundamentally if you're actually measuring it, irrespective of the patient's complaint, you're going to get a higher incidence than if you're only going with the patient's complaint, because you do have an objective measure. You'll see whether there's a change and you'll see exactly what's going on. And no one has ever really done that to my knowledge, other than Matt's group. You very well could have some edema that would be negligible based on a patient's perception. On the other hand, they could be very sensitive to it. So I think that's really the disconnect. In order to improve the accuracy of our assessment of edema, I think physicians should become more rigorous. A simple way to do this is to pick a spot on the ankle 5–1 cm above the level of the lateral malleolus, assess the prevalence of edema and record this information in the patient record for future comparison.
DR GRADMAN:
I agree. It is clear that we still have a lot more to learn. Do either of you wish to speculate on any differences between ACE inhibitors and ARBs in terms of their hemodynamic effects on the vasculature? Are there pharmacologic effects that might translate into some difference in this regard?
DR WEIR:
I am not aware of any known biologic explanations why an ARB might be different than an ACE inhibitor with regard to its effects in attenuating pedal edema by improving venous compliance or capacitance in hypertensive patients. We still don't know how ACE inhibitors or ARBs really work. We do know that they modify the activity of the RAS. They certainly may have other biologic effects that may help attenuate pedal edema.
DR GRADMAN:
Okay, I'd like to go back and elaborate on an issue we touched on at the beginning of our discussion. I'm referring to the use of drug combinations as first‐step therapy. What's your understanding, George, of the type of patient who should get combination therapy up front?
DR BAKRIS:
I think anyone who is 20/10 mm Hg above their BP goal who is not on therapy should be started on combination therapy. In the case of a person with the metabolic syndrome, diabetes, or kidney disease, if they have a BP of 150/90 mm Hg, they should be started on combination therapy because their goal is 130/80 mm Hg. I think that if none of those conditions are present, the person's BP would have to be at least 160/100 mm Hg, before he or she should be considered for first‐step combination therapy. This is what the JNC 7 guidelines said. That's what the kidney guidelines say, and the American Diabetes Association, while it doesn't say that, intimates it and references JNC 7. So I think that is a good rule of thumb. [Note: Although guidelines may recommend first‐step use of a fixed‐dose combination, manufacturers cannot promote such usage without a specific FDA indication.]
Now, which combination would you start with depends on the data. It's evolving. JNC 7 recommends that you start with a combination that includes a diuretic. I think we've learned that this is certainly efficacious, there's no question, but based on changes that you get in some individuals, especially those with the metabolic syndrome or impaired fasting glucose, there's no reason not to start with a CCB/ARB or CCB/ACE inhibitor because you'll get a similar level of BP control without metabolic changes. Now in that situation, diuretics may still be needed as a third‐step agent and there's no reason not to use them in low doses.
DR GRADMAN:
Before we go on to the specific combinations, I'd like to ask a follow‐up question because think your comments are right on target. What if the patient is elderly? What if you are seeing an elderly person who is aged 75 or 80 years and their systolic BP is >20 mm Hg above goal and you are in the process of starting them on antihypertensive therapy for the first time? Does the fact that the patient is elderly have an impact on your decision to initiate a combination, or do the same rules apply?
DR BAKRIS:
No, I think the same rules apply. The only difference is that may start with a lower dose of the combination than would in a younger patient. Let's remember that all of these recommendations are based on individuals with a mean age of around 58 years and a range of about 50 to 70 years. So can this really apply to the 80‐year‐old patient? I think physicians have to act a little more gingerly in their dosing and keep in mind that none of these patients are really going to have substantial diastolic BP elevation; they all have elevated systolic BP. In addition, if BP is decreased too quickly, patients will become symptomatic. I think that is the concern, so physicians go a little slower. And I do, too. But would still use a combination, just at a lower dose.
DR GRADMAN:
This strikes me as a reasonable approach. One of the things I think is also important is to make sure that your patient has been examined for orthostatic hypotension. This is particularly common in elderly and in diabetic patients who may have autonomic neuropathy or dysfunction. You want to know whether the patient is orthostatic at baseline, before you begin drug treatment.
DR BAKRIS:
Absolutely.
DR GRADMAN:
Matt, do you have anything to add in terms of selection of patient populations for first‐step combination therapy? Or with regard to which specific combinations might be used preferentially in different patient subgroups?
DR WEIR:
Well, as I mentioned earlier, I'm a firm believer that everyone should be on something that modifies the RAS unless they have known hypersensitivity reactions or are pregnant or trying to get pregnant. I primarily base the choice of giving a thiazide or a CCB on the patient's sex. I prefer to go the CCB route with men and the thiazide route with women. I do not have any specific approaches that would be altered by age or ethnicity. On the other hand, if patients have chronic kidney disease, I would consider a loop diuretic if they needed volume reduction to help with BP control, particularly if their estimated GFR were <50 mL/min.
DR BAKRIS:
Yes, let me just reiterate, because that's an important point. Physicians need to be looking at estimated GFR, not serum creatinine levels. Thiazide diuretics in the doses that are commonly used in combinations (ie, up to 25 mg of hydrochlorothiazide), really may not work when you get to GFRs <40 mL/min; in fact, it's questionable whether they will be effective in patients with GFRs between 40 and 50 mL/min.
DR GRADMAN:
That is a point that comes up every day. To conclude . . . we have touched on a number of important issues that focus on the difficulty in reaching target BP—the necessity of combination therapy, the importance of tolerability profile, and the specific value of CCB/ARB combinations. If you look at surveys of treated hypertensive patients, you find that goal BP is reached in only a minority with therapies they are receiving in their physicians' offices. I think it is clear that the use of combination therapy, both as first‐step treatment and as add‐on therapy, is critical in improving BP control rates and reducing the frequency of both adverse effects and long‐term complications. Any other comments?
DR BAKRIS:
Well, I think you've covered it all well. I think the only additional information is that combinations are here to stay—their use is expanding. Within a year there are going to be other combinations with β‐blockers and ACE inhibitors and CCBs and β‐blockers, so the whole field is expanding in terms of combinations, and physicians really need to get comfortable using them.
DR WEIR:
I would emphasize the point that George made and add some additional thoughts. I think physicians need to develop more confidence and comfort in the accruing evidence that more prompt control of BP with the employment of fixed‐dose combinations provides an important benefit for patients, particularly for patients who are >20 mm Hg from goal. We know from experience that the single‐agent approach prolongs the time it takes for people to get to goal. Unfortunately, delay in getting to goal increases the risk for cardiovascular events. This has been demonstrated in a number of recently completed clinical trials. This is why the guidelines have expanded the discussion about those patients who are more distant from goal by encouraging the earlier use of fixed‐dose combinations.
DR GRADMAN:
The point that you brought up about prompt BP control is important. The idea today is that it's a key objective not only to get to target BP but to get there reasonably quickly. I used to see patients who resisted starting antihypertensive drug therapy. They would promise to lose weight, restrict their salt intake, and get up every morning and run 10 miles to reduce their BP by nonpharmacologic means. A lot of the time, I used to let them try such therapies for a period of several months before initiating drug treatment. But I don't do that anymore for the reasons to which you alluded (ie, prompt BP control may have a major impact on reducing cardiovascular risk). Now, I am much more likely to start drug therapy immediately, often using combination therapy. I tell them that the nonpharmacologic therapies do work and that if they are successful at lifestyle modification, we will try reducing or even eliminating their drug treatment. We want to promote a healthy lifestyle but not at the expense of prompt BP control.
Disclosure:
This expert panel discussion was supported by Daiichi Sankyo, and each author received an honorarium from Daiichi Sankyo for time and effort spent participating in the discussion and reviewing the transcript for important intellectual content prior to publication. The authors maintained full control of the discussion and the resulting content of this article.
Disclaimer:
The FDA requires that combination products obtain a specific indication for use as first‐step therapy in hypertension or in specific disease states. At present, the only combinations specifically approved for first‐step therapy are Ziac (bisoprolol/HCTZ), Capozide (captopril/HCTZ), Hyzaar (losartan/HCTZ) and Avalide (irbesartan/HCTZ). In the preceding discussion, the authors express their individual opinions regarding the use of various drug combinations both as first‐step therapy and preferentially in certain disease states. These opinions should not be interpreted as recommending off‐label use of any antihypertensive agent or drug combination.