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American Society of Hypertension 20th Annual Scientific Meeting and Exposition
2005年5月14－18日
美国加利福尼亚州旧金山
May 14 - 18, 2005, San Francisco, California The "New Definition" of Hypertension Must Include Overall Risk
Norman D. Kaplan, MD
The highlight of the 2005 meeting of the American Society of Hypertension (ASH) was presented at the opening plenary session by ASH president Thomas D. Giles, MD (Louisiana State University School of Medicine, New Orleans). Dr. Giles presented a proposed new definition of hypertension to include risk factors in addition to an elevated blood pressure. The new definition, prepared by a group including Drs. Michael Weber, Dan Levy, and Bradford Berk, is in keeping with the growing perception that the only way to adequately protect hypertensive patients is to address all of the major cardiovascular risk factors that typically accompany hypertension.This rationale was recently supported in a paper in The Lancet written by members of the investigators from New Zealand who first popularized the concept of basing the judgment of active antihypertensive drug therapy on total absolute cardiovascular risk rather than on an arbitrary defined level of blood pressure.[1] Jackson and colleagues concluded that "Separate management guidelines for raised blood pressure and blood cholesterol need to be replaced by integrated cardiovascular risk management guidelines, and absolute risk prediction scores should be used routinely."
The ASH proposal incorporates this concept, expanding the definition to include overall risk. All of our current guidelines, including the Seventh Joint National Committee report (JNC-7),[2] recognize the importance of overall risk, but the only one that has specifically incorporated such a level of risk to define the need for antihypertensive therapy is the British Hypertension Society's 2004 report.[3] They recommend that drug therapy should be started at levels of blood pressure of 140/90 mm Hg or higher if the 10-year risk of cardiovascular disease is 20% or higher.
The British guidelines for determining cardiovascular risk are based upon the same basic risk factors incorporated in the Framingham Heart Study formula and published as part of the expert panel of the National Cholesterol Education Program.[4] These include age, gender, blood pressure, total and high-density lipoprotein cholesterol, smoking, and diabetes.
Despite the obvious attraction of this concept, some problems seem apparent:
First, it will be very hard to break the longstanding habit of both practitioners and patients of using blood pressure levels as the main criterion for both the diagnosis of hypertension and the decision to begin drug therapy.
Second, there are a number of newly advocated risk factors, including proteinuria, hyperuricemia, and C-reactive protein (CRP), which could improve the accuracy of cardiovascular risk assessment.
Third, there is some question as to the ability of the Framingham formula, based upon a virtually all-white population, to appropriately assess risk in other populations.[1]
I believe these concerns should not hold back the acceptance of the wider definition proposed at the ASH meeting. It will take a long time to erase the simplistic view that the blood pressure level alone is paramount, but there are 2 basic reasons why we should. First, the measurement of blood pressure, as typically performed, is often in error, both overdiagnosing those with a large "white-coat" effect and underdiagnosing the surprisingly large group of people with "masked" hypertension, ie, normal blood pressure in the office but high blood pressure out of the office when measured by automatic ambulatory monitors.
Second, there is no way to deny the overriding importance of other risk factors in determining the risk status of an individual patient, particularly in making the decision to begin antihypertensive drug therapy. We've certainly recognized the need to treat all patients with diabetes or renal insufficiency at blood pressure levels below 140/90 mm Hg. Moreover, the impressive benefits of statin therapy to reduce the risk of both heart attack and stroke in hypertensive patients[5] support the recognition of the critical role of dyslipidemia and the need for its management.
The need for attention to all major risk factors is clearly growing as the incidence of the metabolic syndrome increases in our expanding obese and sedentary population.
Whether or not other risk factors should be incorporated into the current assessment was addressed in other presentations at the ASH meeting. In particular, additional support was provided for the incorporation of proteinuria. Even microalbuminuria has been shown in multiple populations to be as much of a risk factor as elevated blood pressure or dyslipidemia. The evidence for other risk factors, including coronary calcifications (as seen on EBCT), CRP levels, and hyperuricemia, is less impressive, but a number of abstracts attest to their being markers of inflammation and target organ damage.
Obviously, a wide range of other topics was covered in the hundreds of oral and poster presentations. I was particularly impressed with the evidence that additional measures of arterial function and structure are both practical and potentially useful in the clinical management of hypertension. Noninvasive measurements of arterial compliance and stiffness (eg, the Atorvastatin and Amlodipine in Patients with Elevated Lipids and Hypertension results presented by Jay Cohn, MD) were shown to help define the underlying role of blood pressure in such diverse conditions as sleep apnea, aging, and heart failure. From what I saw and heard, such measurements may very well soon be incorporated into routine clinical practice. In the meantime, wide use of home blood pressure measurements was encouraged by the exhibits of multiple home devices that are more accurate and easier-to-use and can be more easily accessed because of pharmaceutical company rebates.
Not surprisingly, a number of presentations addressed issues of antihypertensive drug therapy. There were no major revelations, but a number of presentations documented the need for combinations of drugs for most patients and their multiple benefits on various surrogate endpoints such as left ventricular hypertrophy and endothelial dysfunction. A number of papers addressed the beneficial roles of aldosterone antagonists far beyond their effect on renal sodium handling. And a few papers demonstrated the potential advantages of direct renin inhibitors, which are likely to be the next new class of antihypertensive drugs to be marketed.
One of the areas where little new information was presented was renovascular hypertension. Attention was called to the first randomized controlled trial of intensive medical therapy with and without endovascular stenting, but those results are not expected for another 5 years.
For the first time, a separate portion of the program focused on hypertension in children, emphasizing both its increasing incidence and its usual association with other features of the metabolic syndrome.
Last but certainly not least was the recognition of the amazingly productive career of Friedrich C. Luft, MD, who received the highest accolade of the Society, the Richard Bright Award. Dr. Luft and his associates at the Humboldt University of Berlin continue to be the source for some of the leading research in hypertension, and they richly deserve the recognition.
All in all, it was a very good meeting. Once again, going to ASH was a great way to witness the progress in the field of hypertension.
Amid the attention at this year's American Society of Hypertension meeting devoted to major theoretical topics such as reassessing the very definition of hypertension, there were a number of presentations assessing parameters of importance to actual clinical practice. These ranged from assessment of vascular compliance, particularly in the microcirculation, an early indicator of the onset of cardiovascular disease, to various environmental factors (stress, exercise, temporality) affecting blood pressure. Below are some of the highlights of these presentations.
Improvement in Vascular Compliance With Combination of Amlodipine and Atorvastatin Therapy (AVALON-AWC)
A substudy of the Atorvastatin and Amlodipine in Patients with Elevated Lipids and Hypertension (AVALON)[1] trial suggests that by treating hypertension and dyslipidemia simultaneously with a combination of amlodipine and atorvastatin, greater vascular benefits can be achieved than from treatment with atorvastatin or amlodipine alone.
The AVALON Arterial Wall Compliance (AVALON-AWC) included 667 patients (263 females), aged 24-76 years (average 55), randomized to placebo (n = 183), amlodipine 5 mg (n = 159), atorvastatin 10 mg (n = 154), or amlodipine plus atorvastatin (n = 171) who were followed for 8 weeks. The microcirculation and large conduit arteries were assessed for pulse wave analysis using the HDI/Pulsewave CR-2000 device (Hypertension Diagnostics; Eagan, Minnesota).
The results revealed the following increased in the microcirculation, as assessed by this method:
For amlodipine + atorvastatin, microcirculation increased from 4.61 to 5.50 mL/mm Hg x 100 (P < .001 vs placebo; P = .0298 vs amlodipine).
For the atorvastatin group, microcirculation increased relatively modestly from 4.52 to 4.66 mL/mm Hg x 100.
For the amlodipine group, the increase was more significant, from 4.26 to 4.76 mL/mm Hg x 100 (P < .05 vs placebo).
Also at 8 weeks, similar overall reductions in blood pressure (BP) and low-density lipoprotein cholesterol were seen in all active treatment groups compared with placebo.
Comment: The AVALON-AWC study was based on the theory that because the lipid-lowering agent atorvastatin and the calcium-channel blocker amlodipine each have beneficial in vitro effects on the endothelium, they may have a greater effect on endothelial function and/or arterial compliance when co-administered. This appears to be the case in the AVALON-AWC study.
Endothelial function -- and even more so, arterial compliance -- methodologies are often debated as to their applicability, and all the same uncertainties exist for the measurement methodologies used in this study. Despite reservations as to the validity of these surrogate endpoints, however, the findings of additive benefits on microcirculatory function with amlodipine plus atorvastatin in AVALON-AWC are consistent with preliminary positive outcomes data reported from the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA).[2] ASCOT found a greater reduction in vascular events with amlodipine-based antihypertensive therapy (vs beta-blocker and diuretic) and an additive benefit with atorvastatin when compared with placebo. A more complete and published discussion of the ASCOT findings will be forthcoming in the latter part of 2005.
For some time now there has been debate as to the relevance of stress-related changes in BP. A variety of definitions have been employed in order to designate a change in BP based on exposure to stress as "significant." However, to date stress-related BP changes have not been routinely correlated with specific end-organ damage.
Ingaramo and Santana[3] studied a 67 patient cohort (48 untreated hypertensives and 19 normotensive individuals) with a mean age of 47 ± 1 year. Patients underwent 24-hour ambulatory BP monitoring followed by a 15-minute mental arithmetic test and a computerized version of the Stroop word conflict test. Blood pressure was measured every 5 minutes for 15 minutes during the time of stressful activities. A renal and carotid arteries duplex ultrasound exam, an echocardiogram, and biochemical testing were also performed. Subjects were categorized as exaggerated responders (>/= 25 mm Hg rise in systolic BP, a >/= 15 mm Hg increase in diastolic BP, or a mean BP increase of >/= 20%). Thirty-five of the 67 subjects were exaggerated responders (29/48 hypertensives, 6/19 normotensives).
There was no difference in carotid intima wall thickness, left ventricular mass index, renal resistive index, or 24-hour ambulatory BP patterns between exaggerated responders and nonresponders; however, exaggerated responders had average serum creatinine levels of 92.7 ± 15.5 vs 81.7 ± 15.2 in nonresponders (P = .016)
Comment: Although interesting, this study does not provide a longitudinal perspective on the relationship between an exaggerated response to stress and renal function changes. Carefully conducted long-term studies are needed to characterize the risk of an overly reactive BP phenotypic pattern and end-organ disease.
It is established that physical fitness and regular exercise reduces a major predictor of cardiovascular disease in adults with normal BP or mild hypertension. Clinical studies have shown that moderate-to-intense physical exercise and conditioning, such as jogging, aerobics, or cycling, done on average at least 3 hr/week, can positively impact vascular health as well as reduce arterial stiffness. Physical conditioning in the absence of medication is not, however, as advantageous to the more severe hypertensive patient.
For this presentation,[4] the augmentation index (AIX), a marker of arterial stiffness, was measured in 190 subjects (age range: 21-73 years, 112 hypertensive, 78 normotensive) by pulse wave analysis in the radial artery. Brachial artery diameter was measured by high resolution ultrasound. Habitual physical activity was also evaluated, which assessed work, sports, and leisure time activities.
The results of the study confirmed that hypertensive patients had stiffer arteries than those with normal BP, and also found that of the patients with normal or mild hypertension, subjects with a low level of physical activity had stiffer arteries than those with higher levels of physical activity. For patients with moderate to severe untreated hypertension, however, a correlation between physical activity and arterial stiffness was not nearly as evident.
Comment: These studies suggest that untreated hypertension seems to level out the benefit of physical activity on cardiovascular risk. These results should not undercut the importance of exercise and regular physical activity. Rather, these studies suggest that habitual physical activity has a protective effect on arterial stiffness, but the effect is more pronounced in patients with normal BP or mild hypertension. It may simply be that the long-standing nature of the damage from moderate-to-severe hypertension leaves the blood vessel as a less-than-ideal target for the beneficial effects of exercise. Best practice therapy for any patient with high BP should continue to include appropriate medications, as well as proper diet and physical activity.
It has been appreciated for some time that there can be rather significant time-of-day and seasonal effects on BP. To determine the magnitude of daily and seasonal variations and their clinical impact on measured BP, an analysis was undertaken of 203,927 random BP measurements from 24,904 patients (3 to 7 year period) compiled at 57 Geisinger Health System community practice clinics.[5] General estimating equation logistic regression was used to determine the effect of time of day and month of year on the probability of identifying BP values at or above 4 different levels (systolic BP > 120 or > 140 mm Hg, and diastolic BP > 80 or > 90 mm Hg).
Results for elevated BP were similar for all 4 BP cuts and for this presentation were only reported for systolic BP readings > 140 mm Hg. The odds ratio for the evening (7:00 PM) vs midday (1:00 PM) was 1.26 (P < .001). When analyzed monthly, the lowest BP levels occurred during the summer months and the highest during winter months. These findings were not influenced by age, gender, race, history of hypertension, or treatment status. The study also suggested that in clinical practice there is as much as a 40% variance in BP levels depending on the time of day and month of year. For example, the probability of a systolic BP > 140 for a measurement taken in January at 7:00 PM was 29.6% compared with 21.1% in July at 1:00 PM, a difference of 40%.
Comment: This study reinforces the fact known to many clinicians -- BP values are temporally as well as seasonally dependent. This is not dissimilar to the seasonal nature of ischemic heart disease, where event rates are higher in the winter months. Before settling on a final patient diagnosis of hypertension the clinician should be mindful of such variability. Moreover, the approach to altering therapy in a treated hypertensive patient should recognize the clear effect that time of day has on a particular BP value.
It appears that high blood pressure increases the risk of erectile dysfunction (ED) in males. For this study,[6] 634 young and middle-aged males between the ages of 31 and 65 years (358 hypertensive and 276 were normotensive) were recruited. Exclusion criteria were a history of diabetes mellitus, heart disease, chronic kidney disease, and/or hepatic or vascular disease. After an evaluation of their medical history and hypertension status, patients completed an International Index of Erectile Function questionnaire.
The results revealed a strong link between questionnaire scoring (surrogate for ED) and elevated BP. Overall, 35.2% of the hypertensive patients had some level of ED, and 9.2% of these patients had severe ED (P < .0001). Alternatively, 14.1% of patients with normal BP had some degree of ED with 1.5% of these patients having severe ED (P < .0001). ED was more frequent even in subjects with high normal or prehypertension.
Comment: It is increasingly recognized that a strong association exists between hypertension and erectile dysfunction and now it appears that the gradient for risk begins at high normal BP readings. The first signal of endothelial damage in males with vascular risk factors is that of erectile dysfunction. The endothelium plays a central role in regulating vascular homeostasis of the corpora cavernosa, making the penis an accurate barometer of the body's endothelial function. Clinicians can use ED as a warning signal to detect and treat undiagnosed hypertension at an earlier stage.