Article: Antihypertensive drugs

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Antihypertensive Drugs: Is It All in the Blood Pressure-Lowering Effect?: An Expert Interview With Ronald G Victor, MD

Posted 06/03/2004

Medscape

Editor's Note:

Ronald G Victor, MD is Professor of Internal Medicine and Chief of the Hypertension Division of the University of Texas Southwestern Medical Center at Dallas, where he holds the Norman and Audrey Kaplan Chair in Hypertension. He is also Co-director of the Donald W Reynolds Cardiovascular Clinical Research Center.

Dr. Victor's research focuses on hypertension in special populations, including blacks and patients with chronic renal failure, and the neural mechanisms of hypertension. Other research interests include obesity-related hypertension, cocaine-induced cardiovascular toxicity, cyclosporine-induced hypertension, and metabolic modulation of adrenergic receptor signaling.

Dr. Victor has authored more than 100 articles and book chapters, including the chapter on arterial hypertension in the upcoming edition of Cecil's Textbook of Medicine. He is also a member of the executive committee for the American Society of Hypertension, for which he currently serves as secretary. At the recently held American Society of Hypertension 19th Annual Meeting, Dr. Victor was interviewed for Medscape Cardiology by Linda Brookes, MSc.

Medscape: What do you see as the main issues in the treatment of hypertension today?

Dr. Victor: Hypertension control rates have improved very little in the past 2 decades in the United States, so that currently, of the 50 million Americans with hypertension, only about one third have their blood pressure treated and controlled to a value of less than 140/90 mm Hg. This has raised alarm in the public health community -- despite all the knowledge from clinical trials showing that treating hypertension reduces the risk of premature cardiovascular disability and death and end-stage renal disease, translation of that knowledge into the day-to-day practice of medicine has been problematic. Some of the problem stems from patient compliance, some of it from access to healthcare, and, more recently, it has become apparent that physicians are not adhering to the most current blood pressure management guidelines, which emphasize the importance of blood pressure per se as a controllable cardiovascular risk factor.

So the question is, what are some of the issues involved that we can control? Physicians cannot control many aspects of modern society and the healthcare system, but we can control what we do, to some extent. One of the issues that has presented a problem for us is that in medical schools, the focus for many years was on diastolic blood pressure (DBP) rather than systolic blood pressure (SBP). When I was in medical school, the teaching was that SBP should be 100 plus your age and that it rose as one got older. We have since come to realize that that was completely wrong and that the rise in SBP with age is not a natural part of human biology, but a consequence of Western lifestyle. We now know that the group that benefits the most from blood pressure treatment is older individuals, who mostly have systolic hypertension. So there is a lot of emphasis in the hypertension community on getting the word out that SBP, particularly in people older than 55 years of age, who comprise the majority of hypertensive patients, should be the main focus, with sufficient medications to reduce SBP to 140 mm Hg or below. This important goal is supported by solid evidence from randomized controlled trials.

There has also been concern about physician inertia and complacency. Studies have shown that even for patients who have ready access to healthcare and staff physicians, such as within the Veterans Administration system, despite bimonthly consultations for hypertension, in most of the hypertension-related office visits the doctor did not intensify the medical regimen either by increasing the dose of a drug or adding a different drug to get the blood pressure down to goal. We do not understand exactly what the reason for that inertia is, but it is important to overcome it.

There may be a concern that if you lower the blood pressure too much in older people, coronary perfusion will become impaired. It has been suggested that if DBP is lowered too much, the so-called J-curve phenomenon comes into play, where a patient with underlying coronary disease becomes at risk for myocardial ischemia. It is very important in an older person with isolated systolic hypertension to lower blood pressure slowly. Although we want to get the blood pressure to the goal of around 140 mm Hg or less, that should not happen too quickly. It can be a process that happens over weeks or even months. I believe it is very important to check the blood pressure with the patient standing, not just sitting, especially when assessing an older person. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)[1] did not sufficiently emphasize that the standing blood pressure should be below 140 mm Hg, but not below 120 mm Hg.

Medscape: There has been a lot of discussion recently about how to measure blood pressure, who should do it, etc.

Dr. Victor: I believe it is very important to measure it seated and after the patient has been upright for a while. I think a lot of experienced physicians are concerned about their older patients falling and breaking a hip because their blood pressure is too low. It is probably best to measure it in an elderly patient 3 ways, in seated, lying, and standing positions, with at least 2-3 minutes between each position for the blood pressure to adjust. That provides both the physician and the patient with the secure knowledge that the blood pressure is lowered sufficiently to minimize the risk of heart attack, stroke, and kidney damage, but the pressure is not so low that you worry about overtreating the patient.

Medscape: Is the "white coat" effect seen frequently among the elderly?

Dr. Victor: Yes. The white coat effect has been a very difficult problem to address. Depending on how it is defined, white coat hypertension occurs in up to one third of patients. It seems to become more common as people age. Probably all of us are more concerned about our mortality as we get older, and the vessels are probably stiffer and more reactive to the adrenergic stimulus of the anxiety of going to the doctor, even just to get blood pressure measured. Home and ambulatory blood pressure monitoring are thought to be helpful in diagnosing white coat hypertension, although this is still unresolved.

It is helpful to have patients monitor their own blood pressure because it engages them in their treatment and they take a more active role in evaluating whether there are big differences between the office blood pressure and the home blood pressure. It is very important that patients bring in their home monitoring apparatus to have it checked out against the mercury column and ensure that it is accurate and that calibration is sustained long term. There are some pitfalls with home monitoring. One is that anxious patients often record their blood pressure only when they feel anxious, so you get only elevated readings. Other people want to please the doctor and only record the good readings and throw away the bad. So sometimes the readings are not very accurate. There is also a small subset of patients who become obsessed with and neurotic about their blood pressure.

The best reflection of the total 24-hour period is 24-hour ambulatory blood pressure monitoring (ABPM), an approach that is now approved for reimbursement by Medicare for white coat hypertension. This is the only indication for which it is currently reimbursed by Medicare. Many other third-party payers will pay for 24-hour ABPM and for indications other than white coat hypertension. For eligibility, Medicare requires 3 home readings that show normal blood pressure and 3 office readings showing high blood pressure. There cannot be any evidence of target organ damage, and a patient has to be untreated. These very strict criteria have restricted the use of the device because it is a substantial financial outlay for an office, and must be purchased with accompanying software.

ABPM shows the time interval burden of blood pressure on the cardiovascular system throughout the whole 24-hour period, which correlates better with target organ damage, such as left ventricular (LV) hypertrophy, than casual office blood pressure readings. Most of the outcomes data we have are with casual office blood pressure readings, not with the 24-hour ABPM.

There are at least 2 outcome trials involving 24-hour ABPM that suggest that in people who have strictly defined white coat hypertension, ie, office blood pressure greater than 140/90 mm Hg but normal out-of-office blood pressure on no treatment, the prognosis in terms of cardiovascular risk is indistinguishable from that in people with normal blood pressure. Countering this finding, cross-sectional data in populations with white coat hypertension have shown that these individuals had left ventricular mass intermediate between that of true hypertensives and that of true normotensives. Patients who have white coat hypertension also tend to have other cardiovascular risk factors such as obesity, insulin resistance, and high lipids.

So in the hypertension field it is not clear whether white coat hypertension is totally benign. The recommendation for patients with white coat hypertension is to follow them with either home measurements or ABPM, and if the blood pressure starts to rise it should be treated. Some physicians treat white coat hypertension as though it were hypertension. I do not know whether this is the correct approach, but I have had patients who were not treated for decades because they were said to have white coat hypertension, and whom I am now treating for severe hypertension with progressive renal insufficiency. Clearly, the diagnosis was missed in these patients. I believe that, often, the biggest risk is present in those who come to see me who cannot believe that they could possibly have hypertension. Many physicians are like this; they believe they have white coat hypertension because they have a type A personality. There is a risk of "analysis to paralysis," if you overanalyze your situation.

Medscape: What is the prevalence of white coat hypertension?

Dr Victor: That depends on how you define it. If you define it as a blood pressure level greater than 140/90 mm Hg consistently in the office and consistently less than 120/80 mm Hg (normal) at home, the prevalence will not be as high and that group is likely to have a very favorable prognosis. When the definition of what is normal outside the office is in the 130/80 mm Hg range, the outlook is less clear.

Medscape: Do you believe that some antihypertensive drugs have additional beneficial cardiovascular effects beyond blood pressure lowering?

Dr Victor: Experts differ on how to interpret the trial results. Most of the clinical research has been done on angiotensin-converting enzyme (ACE) inhibitors and, more recently, on angiotensin receptor blockers (ARBs). The best evidence that ACE inhibitors or ARBs have benefits for renal or cardiac protection beyond blood pressure is in patients with type 2 diabetes, and even those findings are subject to different interpretations.

Medscape: How do you interpret them?

Dr Victor: The meta-analysis by Staessen and colleagues[2] and, more recently, by the Blood Pressure Lowering Treatment Trialists Collaboration[3] looked at many different studies and concluded that in these different treatment trials, with different populations and different classes of agent, lowering of blood pressure reduced cardiovascular events and cardiovascular death risk in proportion to the fall in blood pressure. Event reduction seems to level off at a certain point, but the mortality reduction in the Staessen meta-analysis was a straight-line reduction between achieved fall in office SBP and the risk of cardiovascular death. I believe that the cardiovascular protection afforded by lowering blood pressure in people with hypertension is so great that it is difficult to show additional benefit beyond blood pressure lowering; there would need to be a very powerful effect to show that. I think the data are incomplete as to the extent of that additional lowering. I think that it is an interesting, open question that has yet to be fully resolved.

For example, there has been a great deal of controversy about the Heart Outcomes Prevention Evaluation (HOPE) trial,[4] which was not a hypertension treatment trial, where the protection against cardiovascular events and death associated with the ACE inhibitor ramipril appeared to be greater than could be explained on the basis of a very small reduction in blood pressure of about 3/2 mm Hg. In the diabetic subgroup, in the MICRO-HOPE study,[5] the protection against death was even greater than in the group as a whole, and again the reduction in blood pressure was very small (about 2/1 mm Hg). Those who performed the multivariate analysis on those data concluded that it would be very difficult to explain these positive effects on the basis of such a tiny effect on blood pressure. So some of it was due to blood pressure, but some of it must have been due to the blocking of the pleiotropic effects of angiotensin on the cardiovascular system. Against that is the fact that if you plot the HOPE data on the Staessen meta-analysis, it falls within the 95% confidence intervals of the relationship between a fall of even 3 mm Hg in SBP vs cardiovascular protection. So the Staessen group concluded that there is no need to propose any additional benefits for the ACE inhibitors.

There was a very small substudy of HOPE[6] in which 24-hour ABPM was performed on only 38 patients at 1 center in Sweden: 20 patients received ramipril and 18 placebo. In this substudy, 24-hour ABP was significantly reduced by 10/4 mm Hg (P < .03), mainly because of the 17/8 mm Hg reduction that occurred during nighttime, a much greater fall in blood pressure than reported in the overall HOPE trial. The authors of this substudy suggested that because ramipril was dosed at bedtime in HOPE, the peak effect occurred when the patients were asleep. They also implied that the blood pressure was not a very careful endpoint in HOPE and pointed out that it was not the primary endpoint. So they concluded that the fall in blood pressure was greatly underestimated by the main HOPE trial. This 24-hour blood pressure study showed the importance of including that measurement in future studies. Where a benefit of a drug beyond blood pressure lowering is being investigated, it is necessary to have the best measure of blood pressure lowering. Unfortunately the 24-hour ABPM study was only carried out in 20 patients on ramipril, whereas in the main HOPE trial, almost 10,000 patients received ramipril, so it is difficult to extrapolate and know whether that subset of only 38 individuals in the substudy was representative of the whole trial.

Medscape: Dr. Staessen is well known for his belief that blood pressure lowering is the main effect, and some of the HOPE trialists are well known for holding the opposite view. What is your conclusion?

Dr. Victor: I would say that that there is now abundant proof that lowering blood pressure is crucially important in cardiovascular protection. My personal opinion is that there is insufficient evidence to prove that ACE inhibitors have cardiovascular benefits beyond blood pressure lowering. I think the HOPE trial was not sufficiently designed to answer that question, and these kinds of arguments show that to prove some of the alternative interpretations, such as drug A does better than drug B, you have to match the 24-hour blood pressure lowering as carefully as possible by 24-hour monitoring. I think the studies need to include large subsets of individuals who undergo 24-hour monitoring to prove these kinds of points. We do not yet have the information.

One area that I believe is becoming increasingly clear, however, is that compared with beta-blockers, ACE inhibitors and ARBs are advantageous in terms of less progression to diabetes. Whether ACE inhibitors and ARBs have an antidiabetogenic effect or beta-blockers have a prodiabetic effect, or all of the above, is unknown. On the basis of clinical trial evidence, ARBs seem to have an advantage over other classes of drugs in patients with type 2 diabetes, but again, there is a big effect of blood pressure lowering and, by comparison, a small additional class effect. In simple terms, I would say that from the literature to date, it appears that about 90% of the benefit is blood pressure lowering and about 10% is class effect. I think that every time that a class effect is demonstrated, there are alternative interpretations of the data and the magnitude of the effect is open to question. There is one message I would like to get out, and that is to get that blood pressure down.

Medscape: Are there any data showing that diuretics are also diabetogenic?

Dr. Victor: There are data from observational studies demonstrating that both beta-blockers and diuretics increase glucose and insulin levels. That was substantiated by the data with chlorthalidone from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).[7] There is ongoing debate as to how important that is, whether it is a biochemical change or whether it really translates into meaningful cardiovascular risk associated with diabetes. I think that a 4- to 5-year life span of a clinical drug trial for hypertension is too short to evaluate the impact of an increase in the incidence of diabetes over a person's 2-3 decades of adult life. In the context of ALLHAT, however, there was an increased incidence of diabetes and an increase in blood glucose associated with chlorthalidone vs the 2 other main comparators that went on to the endpoint of the trial, the ACE inhibitor lisinopril and the dihydropyridine calcium channel blocker (CCB) amlodipine. The primary outcome was exactly the same with all 3 agents. So you could argue that this shows that all of these classes of drugs are very equivalent.

The controversy comes from the fact that there was greater blood pressure lowering with chlorthalidone than there was with lisinopril. If you look at the endpoint of the trial, the difference was only 2-3 mm Hg, so if you look at the area under the curve for the 5 years, there is clearly a lowering of the blood pressure burden that was greater with chlorthalidone than with lisinopril. So it complicated to start talking about cardiovascular benefit beyond blood pressure. It is difficult to extrapolate to that conclusion, or even to discuss it.

Medscape: What is your opinion about the other ALLHAT results?

Dr. Victor: One point I want to emphasize is that in black patients, the risk of stroke was 40% higher in those randomized to lisinopril than in those randomized to chlorthalidone, and it has been suggested that caution must be used in administering ACE inhibitors in black hypertensive patients. I do not agree with that conclusion, because if you look at the blood pressure difference, blood pressure was lowered a lot more with chlorthalidone than it was with lisinopril in the black patient subset, and that could have a big effect on stroke, given the importance of blood pressure as a risk factor for a stroke. It has been known for years that as monotherapy, ACE inhibitors yield a smaller drop in blood pressure in most black hypertensive patients than in most nonblack hypertensive patients, but there is a lot of variability from one African America patient to another, so you cannot generalize. Plus, if you add a low-salt diet or a low-dose diuretic, the synergistic effects on blood pressure in almost all, if not all, ethnic differences disappear. So clinical trials of monotherapy are artificial, because most of us who practice medicine would not use monotherapy for this sort of situation. ACE inhibitors are sometimes very well indicated for African American hypertensive patients, but they should be combined with the appropriate diuretic treatment or low-salt diet, probably diuretic being the most important.

In the African-American Study of Kidney Disease and Hypertension (AASK) trial,[8] which studied nondiabetic African American patients, the ACE inhibitor ramipril was reported to be superior to amlodipine and also somewhat superior to metoprolol in terms of reducing the rate of decline in renal function in that hard-to-treat group. A few caveats need to be stated, however. One is that the benefit of ramipril over other drugs was only seen in the subset of patients who had proteinuria at baseline and who therefore had more advanced renal insufficiency. It is not clear from the trial whether there was a difference in the drugs in the large subset that did not have proteinuria at baseline.

The second point, which to me was probably more important than the main outcome of the trial, was that these were African American patients who already had renal insufficiency and very high blood pressure at baseline, thought to be one of the hardest groups to achieve blood pressure goals. The study investigators showed that if you combine any of these 3 agents with appropriate diuretic therapy and enough additional agents so that the patients are adherent, you can get the blood pressure to goal in the vast majority of the patients. If you look at the blood pressures in AASK, you see that the investigators achieved very good control of blood pressure. To me that is the most important outcome of this trial.

The other point is that the ASSK results do not indicate that dihydropyridine CCBs should be avoided in these kinds of patients. They just demonstrate the importance of using an ACE inhibitor and a diuretic as first-line therapy. Most experts believe that renal insufficiency is an indication for a loop diuretic such as furosemide, given in twice-daily dosing. The third-line agent could either be a dihydropyridine CCB, once the ACE inhibitor has been fully titrated, or perhaps a beta-blocker. I prefer a vasodilating beta-blocker such as carvedilol or labetalol because they are more powerful than the other beta-blockers. It usually takes 3 or 4 drugs to get these patients' blood pressure to levels below 140/90 mm Hg.

Medscape: Should the goal be 130/80 mm Hg?

Dr. Victor: The current recommendation is < 130/80 mm Hg. The AASK data could not substantiate that recommendation.

Medscape: This is the goal in the current guidelines.

Dr. Victor: Most hypertension experts believe that lower is better in terms of blood pressure and reducing progression to end-stage renal disease and reducing the risk of cardiovascular events. In AASK, however, patients achieved average blood pressure of 141/85 mm Hg in the usual blood pressure group and 128/78 mm Hg in the lower blood pressure group, and no difference in slowing progression of hypertensive nephrosclerosis could be shown between those groups, although the study was probably underpowered to do that.

Medscape: So what do you think about current guidelines?

Dr. Victor: In a diabetic patient, it is clear that the blood pressure goal should be below 140/90 mm Hg, although it is hard to substantiate this with evidence from real data.

Medscape: Do you aim to get blood pressure down to 130/80 mm Hg in these patients?

Dr. Victor: I go for the lower goal in the setting of renal insufficiency, but you do not want to get to this blood pressure goal too quickly. So I use 140/90 mm Hg as the initial goal and then get down to the stretch goal of 130/80 mm Hg as the next step. It is done gradually to give the homeostatic mechanisms time to catch up. I think there will be more data coming out about how low we should get the blood pressure. Our first aim is to prevent renal insufficiency and treat the blood pressure early; to me, that is most important. An ounce of prevention is worth a pound of cure.

Medscape: Is there any particular research that you are looking to in the future to clarify this?

Dr. Victor: There are important studies, such as the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), that are looking at different combinations of regimens, which will help us to determine which combination is right for each patient. Until we know much more about the basic pathophysiology of hypertension, most patients are going to require larger numbers of drugs.

Disclosure: Dr. Victor has disclosed that he received grants for clinical research and educational activities from Novartis and Biovail. He has served as an advisor or consultant for Bristol-Myers Squibb and Sanofi-Synthelabo Inc. Dr. Victor reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity.

Disclosure: Linda Brookes has no significant financial interests or relationships to disclose.

Medscape Cardiology 8(1), 2004. ? 2004 Medscape