Abstract
Following a symposium on hypertension sponsored by the National Heart, Lung, and Blood Institute in Chicago, IL on October 3, 2001, a panel was convened to discuss various aspects of hypertension treatment. Moderating the panel was Dr. Marvin Moser, Clinical Professor of Medicine at The Yale University School of Medicine. Panel members included Dr. George Bakris, Professor of Preventive Medicine and Director, Hypertension/Clinical Research Center at the Rush‐Presbyterian‐St. Luke's Medical Center in Chicago, Illinois and Dr. Henry Black, Professor of Medicine, Associate Vice President for Research, and Chairman of the Department of Preventive Medicine at Rush‐Presbyterian.
DR. MOSER: I would like to present several cases and review management problems. The first is a 56‐year‐old woman with a negative family history for diabetes and high blood pressure (BP). She is a non‐smoker, is not obese, is active physically, and is asymptomatic. A routine exam showed a BP of 155/95 mm Hg. This was repeated three times at the first visit, with no variability. Cholesterol was 225 mg/dL, low‐density lipoprotein (LDL) cholesterol 120 mg/dL, and high‐density lipoprotein (HDL) cholesterol 52 mg/dL. Blood urea nitrogen was 18 mg/dL, creatinine 1.2 mg/dL, uric acid 6 mg/dL, and glucose 82 mg/dL. Urine was negative for protein on a dipstick, and otherwise negative. The electrocardiogram (ECG) was normal.
Dr. Black, what additional procedures would you like to perform before you treat this patient? Tell us how you would classify her as to risk and the immediacy of intervention.
DR. BLACK: I wouldn't do anything further, except perhaps to look into her history to make sure that the BP has been gradually increasing over time.
DR. MOSER: The last time she had a BP taken was 4 years ago.
DR. BLACK: And what was it?
DR. MOSER: No record.
DR. BLACK: Typical. The reason I ask is that this is a very typical history of someone with essential hypertension.
DR. MOSER: Okay...you decided not to do any procedures. Would you just tell her to come back in 2 months and check the BP again?
DR. BLACK: Well, I would assume she had had a careful physical exam.
DR. MOSER: Yes.
DR. BLACK: And she did not have abdominal masses or abdominal bruits, nor anything like a rapid pulse rate to suggest thyroid disease or any other secondary causes.
DR. MOSER: Nothing at all.
DR. BLACK: I would certainly see her again in about 1 month to check her pressure, although that is a little sooner than recommended. After that, I would probably see her again in 1 month. If the average of the pressures on those visits is >140 mm Hg systolic and/or >90 mm Hg diastolic, I would classify her as a stage I hypertensive. If it were between 130 and 139 mm Hg and 85 and 89 mm Hg, I would classify her as high‐normal. In either case, since she has no risk factors other than a borderline age criterion, I would consider her a low‐risk individual to whom I would unambiguously recommend lifestyle modification.
DR. MOSER: But she doesn't smoke, she's active and thin... what lifestyle changes might be helpful?
DR. BLACK: One cannot do much, other than perhaps reduce salt intake if she's a salt user.
DR. MOSER: Again, she has told you, “I don't use any salt; I never use it in cooking, and I don't use it at the table.”
DR. BLACK: Then I would actually consider treating her with the drug class that has the fewest side effects. Here is someone who really is asymptomatic and feels well. I would not want to make her feel worse with treatment. Now, what medication would that be? That is an important question.
DR. MOSER: You tell me.
DR. BLACK: Well, I think there are two options. She's white. A low dose of a diuretic or perhaps an angiotensin receptor blocker (ARB) would be the medication I would choose. An angiotensin‐converting enzyme (ACE) inhibitor also would be an option. The problem with an ACE inhibitor is that older women in particular, (although she is not really old), have a higher incidence of cough than do any other demographic subgroups. But these would be my choices.
DR. MOSER: Okay, you would check her BP over 2–3 months, you would treat her if the BP stayed above 140 mm Hg.
Dr. Bakris, what about home Bps and ambulatory monitoring? Why not obtain an echocardiogram? The ECG was negative, but Maybe she has early left ventricular hypertrophy (LVH) that can be picked up on an echo. Isn't this important?
DR. BAKRIS: Before I answer that question, let me ask you a question. Does she have any retinopathy?
DR. MOSER: Unfortunately, the world is such that very few doctors look at the retina.
DR. BAKRIS: Well, they should.
DR. MOSER: However, as you know, if she is not a diabetic and has stage I or grade I hypertension, her fundi May show some arteriolar narrowing, but that probably will not be very helpful in determining the urgency of treatment. We all look at fundi, but in a patient like this, it is very hard to detect definite changes.
DR. BAKRIS: Correct.
DR. MOSER: Dr. Bakris, what difference would it make? What if we saw some arteriovenous nicking? That is possible in a patient this age with this type of BP. Would that change your approach?
DR. BAKRIS: Yes, it would change my approach somewhat. It would tell me that she has had an elevated pressure for a fairly long period of time. And it might lead to earlier treatment.
DR. MOSER: You would not wait 2 or 3 months to treat her?
DR. BAKRIS: I would basically do two things. I would bring her back, as Dr. Black suggested, in 1 month and recheck her pressures. If they were similar or a little lower, I would either do 24‐hour BP monitoring or suggest investing in a home BP machine and have her check her Bps at home, then take a look at the pressures over time. When she returns in another month, I would not expect lifestyle changes to have impacted her pressure very much. If we did a 24‐hour monitor, we would get a quicker response, but the home Bps give us an ongoing picture. If her morning Bps at home continued to hover around 140/90 mm Hg, even if at about 138/80–85 mm Hg, I probably would treat her. In the absence of edema, diabetes, and other risk factors, I probably would start her on an ARB as my first choice.
DR. MOSER: All right, there are a couple of points. What happens if you do ambulatory monitoring at considerable cost and possible annoyance, and you get a daytime reading of 130/82 mm Hg and a nighttime reading of about 126/80 mm Hg (some dipping, but not much)? These are definitely within the normal range, even for ambulatory monitoring. However, in your office, on two or three occasions, her pressures remain at 145–150/90–95 mm Hg. Are you going to treat her, or are you going to say that this is just white coat hypertension, forget it, and go about your business?
DR. BAKRIS: It would change my aggressiveness. It would not change what I would do, but it would change how quickly I do it. Based on data from the recent article in The New England Journal of Medicine on mortality in people with high‐normal pressures, I would definitely want her pressures somewhat lower.
DR. MOSER: As an aside, how do you feel about home Bps in general?
DR. BLACK: I'm an outlier; I don't use them. If people want to use them, I don't stop them, but I almost never pay any attention to them.
DR. MOSER: In other words, if I brought in 20 readings at 130–120 mm Hg and in your office it was always 150 mm Hg, you would use the office pressures for guidelines in therapy.
DR. BLACK: We need to educate people that what is normal at home is not what is normal in the office. The average difference is about 12/7 mm Hg. For somebody who is 135/80–85 mm Hg at 10 p.m., after having two drinks and just waking up from a boring baseball game, to say the pressure is normal is wrong. I think it gives misinformation, it makes some people a bit neurotic about their pressure, and I pay almost no attention to it.
DR. MOSER: Then the studies that appear to indicate that outcomes are improved when home Bps are telephoned into a computer and stored May not be important?
DR. BLACK: That is a little different. One of my concerns about home readings is the bias patients have about telling you what they want you to know.
DR. MOSER: There are some data that claim that this May not be true.
DR. BLACK: Well, there are old papers that did describe biased reporting, and I am concerned about this.
DR. MOSER: The computer readout reports 20 readings that are below 140/90 mm Hg, but you still get readings higher than 145/95 mm Hg in the office.
DR. BLACK: I am simply not impressed, I do not particularly care what happens at home, unless Bps are too low.
DR. MOSER: Dr. Bakris, you agree?
DR. BAKRIS: No, I disagree. I think that if you tell people to monitor home pressures and don't give them any guidance, then it's meaningless. I wouldn't do that. What I do first is insist that the patient bring the machine in and we calibrate it. I tell patients that the only Bps we are interested in are the ones in the morning, because of the higher cardiovascular event rate at that time. They can measure it at any time they want—preferably between 6 a.m. and 10 a.m., and not after they've had drinks or eaten a full breakfast or anything like that—and they should always do it twice. These are the readings that I consider.
DR. MOSER: Would these readings change your approach?
DR. BAKRIS: Well, it changes my approach only if I get dramatically low readings at home and dramatically high readings in the office. But to tell you the truth, I've never seen that, except in one patient whom I sent for biofeedback.
DR. BLACK: It is also interesting that we berate ourselves for not taking BP in the office accurately, but we have no quality control at all about Bps taken in the home.
DR. BAKRIS: That's right.
DR. MOSER: I agree that home pressure May have limited value, but there are some patients who want to know what their pressures are and in those cases, its important that they be encouraged to measure them. These readings also serve as reinforcement if they are controlled. Also, in some situations patients will complain of dizziness when their pressures are high rather than low, so there is probably some benefit to home BP recordings.
DR. BLACK: I base my therapeutic decisions on office readings because that is what we know.
DR. BAKRIS: And, by the way, so do I.
DR. MOSER: All right. Three months pass by and our patient's Bps are still over 145/90–95 mm Hg, but you now have this 24 hour reading that says let's wait a minute, the Bps are normal. What do you do?
DR. BLACK: I think you are in a very common dilemma. We ought to follow on our own rules. She is classified as stage I and is below 60 years of age. We can go for 6–12 months without specific pharmacologic treatment. If she had normal ambulatory pressures, I would feel much more confident doing that than if her pressures were high. If they were high—especially if she had retinopathy—I would treat much sooner. I think our rules are wise. If, at the end of 3 months, Bps are not higher, I would wait. At 6 months, if they are higher, i.e., >160 or >100 mm Hg—stage II—treatment is indicated. If not, we can wait for 12 months and then begin specific medication. These are reasonably well considered guidelines.
DR. MOSER: I'm not so certain that I agree. Both of you are vigorous therapists who believe in treating hypertension before microproteinuria is noted and before there is evidence of LVH. Are you going to wait for 1 year and possibly risk further vascular changes before beginning therapy? I am aware that the odds of developing clinical evidence of a cardiovascular event within 1 year in a low‐risk patient are very low, but what about slow progressive changes that we cannot detect clinically?
DR. BLACK: Because she is at such low risk, with no risk factors other than hypertension, the likelihood of her having an event within 1 year, while I sit and watch, is slim to none. However, if that were my BP, I would reduce it.
DR. MOSER: You would treat yourself after a month or two?
DR. BLACK: Hypertension is not an asymptomatic disease. There is a series of very subtle but clearly definable effects on the quality of life.
DR. MOSER: Then why would you not treat this woman the way you would treat yourself?
DR. BLACK: Well, because I cannot prove benefit in this type of case, and you propose a scenario in which I have to use my gut, not my brain.
DR. MOSER: Okay. Well, medicine is intuitive—why not use a gut feeling based on knowledge but not definitive data?
DR. BLACK: That's right, it's an art, not a science.
DR. MOSER: What do you believe? There are data on people who have so‐called “white coat hypertension” in the office and normal Bps at home who show increased vascular resistance, left ventricular dysfunction, and some of the metabolic changes noted in hypertensive patients. We do not have long‐term treatment outcome data on these patients, but I intuitively believe that they should be treated.
DR. BLACK: My approach to this is probably the same as yours. I consider white coat hypertension a way station between normotension and definite hypertension. There is clear evidence from many sources that these people are not the same as normotensives. These are the people we treat with lifestyle modifications if we're concerned about possible side effects or cost, but we treat with medication if Bps remain elevated.
DR. MOSER: George, would you go along with treating this patient if, after 2 months of checking pressures with or without an ambulatory monitor, her pressures remained elevated?
DR. BAKRIS: Well, I think what Henry says is unfortunately the truth.
DR. MOSER: Why unfortunate?
DR. BAKRIS: Because I would do exactly what he said. If I were in this situation, I would treat myself. If you follow present national guidelines, you would not treat this woman for 6 months to 1 year. You would simply follow her, without specific medications. Admittedly, studies that I have seen that describe this kind of patient in terms of natural history suggest that the probability of something happening to her is about equal to the probability of lightning striking me.
DR. MOSER: In the short run.
DR. BAKRIS: Yes, in the short run.
DR. BLACK: Yes, in the short term.
DR. BAKRIS: If she were still at this BP level.
DR. MOSER: However, as we have noted, there May be changes in the endothelium over a year's time that you cannot detect.
DR. BAKRIS: That is a self‐fulfilling prophecy because the more you look, the more you will find.
DR. MOSER: We have somewhat differing points of view on the time we would wait to begin therapy. Let's get to specific therapy when we do decide to treat. What about starting this woman on a low‐dose diuretic?
DR. BLACK: There is nothing wrong with that approach.
DR. BAKRIS: That would be my alternative.
DR. MOSER: This is an alternative that is well tolerated and probably as effective as other agents in a high percentage of patients.
DR. BAKRIS: No argument at all.
DR. MOSER: Let's say that didn't work. She takes 12.5 mg of hydrochlorothiazide and comes back in 3 months. Her BP is still about 140–145/90 mm Hg; would you wait another 3 months before changing therapy?
DR. BAKRIS: I wouldn't wait. Three months is an adequate time to see a response. I would double the dose in this case.
DR. MOSER: Okay, you would go to 25 mg per day.
DR. BAKRIS: And if that didn't work in a few months, I would add a second agent.
DR. MOSER: And the second agent would preferably be an ACE inhibitor or an ARB?
DR. BAKRIS: It would be an ACE or ARB.
DR. MOSER: How about a β blocker?
DR. BAKRIS: Well, my feeling about β blockers is that they are really not as well tolerated as ACE inhibitors or ARBs.
DR. MOSER: So this patient would probably be on a diuretic and May require an ACE inhibitor as an additional therapy—or May respond to an ACE inhibitor or an ARB and require the addition of a diuretic to be maintained at BP levels as close to 120/80 mm Hg as possible. The odds are that goal levels of BP will be achieved and maintained with this type of therapy, without any adverse reaction.
DR. MOSER: The second patient: a 76‐year‐old female, 120 pounds, 5'5”, active, asymptomatic except for a dull morning headache. Father and mother both had hypertension but died at ages 85 and 87. Her BP has been hovering at 170–175/80–85 mm Hg for the past 3 years, and there were some voltage criteria for LVH on an ECG. It was interpreted by her doctor as normal, and because she was thin, the voltage was considered to be within normal limits. Urine was negative, cholesterol 244 mg/dL, HDL of 70 mg/dL, and LDL of 112 mg/dL. What do you do? Any further workup, or do you have enough information to warrant proceeding with treatment?
DR. BLACK: What about her physical exam?
DR. MOSER: Physical examination was negative except for a grade 1 systolic murmur at the left second interspace.
DR. BLACK: I would do nothing further. She clearly needs treatment.
DR. MOSER: What about an echocardiogram?
DR. BLACK: What are you going to learn that would change what you do?
DR. MOSER: You don't think an echo should be done?
DR. BLACK: No, not at all.
DR. MOSER: Dr. Bakris?
DR. BAKRIS: I would agree, especially in light of what you just said. How is this procedure going to change a treatment approach?
DR. MOSER: We all know that ECGs are not very sensitive in picking up early LVH. If you really want to detect LVH, you need an echo, don't you?
DR. BLACK: Of course.
DR. BAKRIS: That's fine, but again, how is a positive or a negative echo for LVH going to change the approach to treatment?
DR. MOSER: It probably will not change what I would do, but a lot of experts do it routinely.
DR. BLACK: If she is in stage II isolated systolic hypertension, she needs treatment. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study,* which is a comparative study of different drugs in patients with LVH suggests that an ARB based regimen reduces strokes more than a β blocker based program and fewer cases of new onset diabetes occur in the ARB group. Most medications that lower BP will regress LVH if it is present. (*The LIFE study was published after this discussion was held).
DR. MOSER: Are you saying that any drug we choose, except for a vasodilator, is going to have a beneficial effect on BP and LVH—that it probably doesn't make any difference whether or not we detect early evidence of cardiac enlargement?
DR. BLACK: Right.
DR. MOSER: Okay. I agree. Do we need standing Bps a couple of times to see whether she has postural changes?
DR. BLACK: Only if she were dizzy, which hasn't been mentioned.
DR. MOSER: No, she's not dizzy.
DR. BLACK: Then I would ignore home pressures. If these get her more involved in her treatment, that's fine, but she seems like a compliant patient and May not need this type of reinforcement.
DR. MOSER: You would treat this patient based on office Bps. We probably will agree that a low‐dose diuretic would be a good initial choice, but that a goal BP, of <140 mm Hg, will probably not be achieved in a high percentage of patients with this therapy alone. Based on a large European study, a dihydropyridine calcium channel blocker (CCB) might be another choice. My own feeling is that a combination of a low‐dose β blocker/diuretic, an ACE inhibitor/diuretic, or an ARB/diuretic would also be acceptable and effective choices. A caveat: although we advocate a goal pressure of <140 mm Hg in the elderly patient with isolated systolic hypertension, this is not readily achievable in a large number of patients. Many times, it is only possible to reduce pressures from about 170–180 to 150–160 mm Hg before a patient will “feel funny.” In these cases, it May be advisable to back off and keep the patient on the same therapy for 3–6 months. After that time, therapy can be increased in an attempt to lower BP further. We should remember that the benefits noted in the clinical trials were achieved with a systolic BP reduction of about 12–15 mm Hg.
DR. BLACK or DR. BAKRIS: Any further comments about this case?
DR. MOSER: The last case is a 46‐year‐old male, 165 pounds, 5'4”, referred to you by his daughter to get another opinion. He is sedentary, and there is a family history of diabetes and hypertension. His father died at age 55 of a myocardial infarction, and his mother at 79 of diabetes. He has been healthy, with no symptoms other than occasional shortness of breath on activity. He ignores this. His Bps are 150–160/95–100 mm Hg. He has recently been started on a long‐acting nondihydropyridine CCB, and his Bps have been about 140–145/85–90 mm Hg. The doctor has assured him that the therapy is successful, and that he is doing well. His physical examination is essentially negative. Fundi show grade I–II changes with some arteriovenous nicking. Routine urine testing was negative, blood urea nitrogen was 22 mg/dL, creatinine 1.4 mg/dL, and glucose 104 mg/dL. He is on antidiabetic therapy with a glycosylated hemoglobin of 7. The ECG is now normal but had previously shown evidence of LVH.
DR. BAKRIS: So he is diabetic.
DR. MOSER: He is a diabetic, and has been told that he is under control. He has no obvious evidence of progressive renal disease. His LVH has improved. He has been told that everything is fine, and his Bps are 140–145/85–90 mm Hg.
DR. BAKRIS: Well, first of all, he is not under control with a hemoglobin of A1c of 7.
DR. MOSER: This, of course, should be about 5.5 or 6.
DR. BAKRIS: Exactly.
DR. MOSER: All right, what do you do? Any further tests?
DR. BLACK: None that I can see.
DR. MOSER: Would you want a determination of microproteinuria, Dr. Bakris?
DR. BAKRIS: Definitely. You said his dipstick was negative?
DR. MOSER: Dipstick was negative.
DR. BAKRIS: Well, I would like to know if there is less than 300 mg/day of protein in the urine, but that will not affect my therapeutic decisions.
DR. BLACK: I would do the same thing that I suspect you, or almost anyone else would. I would add a second agent, which would be an ACE inhibitor or an ARB. I have a different goal BP in this case. I do not consider a 140–145‐mm Hg systolic BP controlled. I also would not consider the 85–90‐mm Hg diastolic controlled in a diabetic patient. Accepting numbers like this, which are close to goal, might appear to be the easy way out, especially in someone on a single agent. But we know we can do much better if we change or add medications. Data indicate that this type of patient should be controlled at 130–135/80–85 mm Hg.
DR. MOSER: Would you put him on an ARB or an ACE inhibitor, or doesn't it matter?
DR. BLACK: Frankly, I would probably put him on an ACE inhibitor, in addition to his present therapy. I don't think there is much difference between an ARB and an ACE inhibitor, but if I'm an evidenced‐based type, I will have to go with the evidence we have. We have good data on benefits with renal disease in diabetes, but few data thus far on coronary heart disease outcome with ARBs. Other studies will probably show us that ARBs do just as well in reducing cardiovascular disease morbidity/mortality, but these data are not available at present.
DR. MOSER: If you did a dipstick for microproteinuria and it was positive—let's say between 30 and 300 mg/day—would you then say that an ARB has to be used to prevent progression of microproteinuria?
DR. BLACK: Well, we have several trials that support this, but we have nothing negative about ACE inhibitors. I think the mechanism is the same, and the results May be the same.
DR. MOSER: So you would leave him on a CCB and add an ACE inhibitor or possibly an ARB. If, 3 months later, the Bps are still 140/90 mm Hg, what would you do?
DR. BLACK: I would titrate up with the drugs that he is being given. I would probably use a fixed low‐dose combination, so that he takes one pill.
DR. MOSER: Okay, 3 months later, his Bps are still not at 130–135/80–85 mm Hg. Would you add another drug?
DR. BLACK: Yes, I would add another drug; I would add a diuretic.
DR. MOSER: I agree that a diuretic is clearly indicated, and I would consider using a combination ARB/diuretic or ACE inhibitor/diuretic in addition to the CCB, or I would stop the CCB and see if one of the combinations would work by itself.
DR. BAKRIS: I would agree with all that. What I would have done, though, is probably go to a combination of an ACE inhibitor/CCB somewhat earlier. I would also limit his sodium intake so as not to blunt the effects of the ACE or ARB. However, you can make the point that sodium reduction is not vital if I add a diuretic, which is what I would do.
DR. MOSER: Now, what if this patient had had a creatinine of 2.3 mg/dL and a definite 2+ protein on a dipstick. He's on a CCB. Would you stop it and use an ARB and a diuretic? Or would his management be the same as it would be if there was little evidence of nephropathy?
DR. BAKRIS: Based on recent data, first I would want to know if it is a dihydropyridine or nondihydropyridine CCB. I definitely would stop a dihydropyridine, but not a nondihydropyridine, and I definitely would add either an ACE inhibitor or an ARB and a diuretic.
DR. MOSER: Would you do this on the patient's first visit to you as a consultant?
DR. BAKRIS: Right away. In fact, an ACE inhibitor/diuretic or an ARB/diuretic should be part of the regimen. I would titrate to higher doses fairly quickly and make sure I achieved Bps below 130/80 mm Hg.
DR. MOSER: So, based on recent evidence in diabetics who already have definite proteinuria and even a slight elevation in creatinine, you would use an ARB and a diuretic in an effort to achieve BP control and slow down progression to end‐stage nephropathy. But you would also continue the CCB if this had been used initially.
DR. BAKRIS: Yes. Actually, if BP were not well controlled—if goal BP's were not achieved—I would probably add a β blocker.
DR. BLACK: One of the things that's so artifical about trials, and we have to remember this, is that they May prevent us from using drugs we would use in practice. There is just so far that we can take trial results with respect to how much they tell us. You would never manage a complicated patient like this without using all the classes of medications at your disposal. Trials don't let us do that.
DR. MOSER: Of necessity, trials involve rigid protocols.
DR. BLACK: They have a lot of value, but they do restrict us. So, in this patient, management May become complicated, but this will prove to be worthwhile if Bps can be lowered to the 130–135/80–85 mm Hg level. This will require multiple drugs.
DR. MOSER: Finally, another scenario. Dr. Bakris, what if our last patient came to you having stopped all of his medication? The creatinine was 1.8 mg/dL and the protein was 2+ on a dipstick.
DR. BAKRIS: You mean, he had been taking medication and stopped before his family got him to come to me?
DR. MOSER: Yes. He was on a CCB and, 1 year ago, on a β blocker. He stopped it all.
DR. BAKRIS: Because?
DR. MOSER: He just got tired.
DR. BAKRIS: Well, I would basically educate him as to what these drugs should be doing for him, what he can expect as an outcome if he doesn't follow the program. I would talk about cardiovascular risk reduction with ACE inhibitors and about ARBs in diabetic patients with some evidence of kidney involvement.
DR. MOSER: Would you start him on an ARB/diuretic?
DR. BAKRIS: I would start him on an ARB/diuretic right away—something like Hyzaar 100/25 mg or Avalide 300/12.5 mg.
DR. MOSER: All right. He doesn't respond to that in terms of getting Bps as close to 120/80 mm