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Microsoft word - hypertension editorial individualized therapy.doc

Individualized therapy for hypertension
( a shorter version of this was published in J. David Spence M.D., FRCPC, FAHA
Stroke Prevention & Atherosclerosis Research Centre 1400 Western Rd., London, ON, Canada N6G 2V2 Phone: 519-663-3113; Fax 519-663-3018; email The recent publication of the Blood Pressure management of resistant hypertension7, 8. As Lowering Arm of the Anglo-Scandinavian Cardiac pointed out by the authors of ANBP2, “In ALLHAT, 32 percent of the patients were non- occasioned a flurry of media pronouncements and Hispanic blacks, 16 percent were Hispanics, and 47 editorials2 contending that now the truth is known, percent were non-Hispanic whites, whereas in and that “newer” therapies – calcium channel ANBP2, almost the entire study population was antagonists and ACE inhibitors − are more effective white (95 percent)” 9 (and less than 2 % had African than “old” therapies for hypertension – beta- ancestors; personal communication, Dr. Lindon blockers and diuretics. In the words of the great Wing, 2003). In ASCOT-BPLA, only 5% of the wordsmith Yogi Berra, this represents “déjà vu all subjects were “ethnic minorities: mainly South over again”. A similar flurry of media Asian or Afro-Caribbean”10; only 2.4% had African pronouncements, but in the opposite direction, was ancestors (personal communication, Dr. Neil Poulter, 2005). Thus, it seems that there is no Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial3, which showed that diuretics were “the best” therapy for In a paradoxical way, precisely because there were hypertension. Largely un-noticed amidst all this so few patients in our region with ancestors from fuss was the second Australian National Blood Africa, and they therefore stood out, we had the Pressure study (ANBP2), which followed closely on opportunity to learn about this in London, Canada. the heels of the ALLHAT trial4, and, like ASCOT- For 20 years I was the physician of last resort for BPLA, also showed that ACE inhibitors were better resistant hypertension for Southwestern Ontario, than diuretics. So what are these trials trying to tell then a catchment area of ~ 1.8 million people. During that time I saw over 10,000 patients referred for resistant hypertension. Included in the referrals The fundamental fallacy underlying all this were patients from a nearby community, North nonsense is the assumption that all patients are the Buxton, Ontario, which had been a terminus of the same, and therefore that there exists a single “best Underground Railroad - an escape route for slaves therapy” for all hypertensive patients. We should ( Whereas patients with African ancestors made up only 1% of It has been clear for many years that patients with our clinic population, they accounted for 40% of African ancestors, on average, had lower levels of our patients who needed adrenalectomy for primary plasma renin than did patients without African hyperaldosteronism11. This >10-fold disproportion ancestors, and that patients with African ancestors may in part be related to selective pressures responded better to diuretics5. African-Americans conferring an advantage on people who could retain bear a disproportionate share of the stroke burden in salt and water in the heat of the African continent, the Stroke Belt of the United States; although much where Arab traders carried salt, like gold, in their of this difference may be due to smoking, diabetes saddle bags. Further selective advantage may have and education6, it seems likely that genetic arisen in survival of the Atlantic crossing in the heat differences in hypertension must account for a and privation of slave ships, and while working substantial proportion of the difference. through the mid-day heat on cotton plantations in Investigation of this phenomenon reveals that the Southern United States12. A recent study of several genetic variants are involved in this hypertension in Sub-Saharan Africa found that difference5. It has also been clear for many years urban Africans had more hypertension than did that measuring plasma renin is very helpful in the rural Africans13; could air conditioning explain treatment: amiloride20. Among monogenic disorders causing hypertension, low-renin hypertension is particularly prominent21. A recent study confirmed When our Hypertension Clinic was instituted in that aldosterone, and the ratio of aldosterone to 1977, the algorithm used (upon the recommendation renin, were more important among black than of Dr. Adam Linton) for outpatient investigation of our patients was based on the observation by Wallach et al 14 that stimulated plasma renin levels Although a disproportionate number of the patients were more useful than random levels of plasma I have seen with primary hyperaldosteronism had renin. By 1980 we had identified over 100 patients African ancestors, I have also seen patients with with stimulated plasma renin activity less than 1 ng/ml/hr. Thinking that we were finding patients hypertension. Thus, treating patients solely on the with Conn’s syndrome, we began, in 1980, with the basis of the color of their skin is inappropriate. help of Dr. Al Dreidger, a Nuclear Medicine What is appropriate, in patients with resistant colleague, to try to identify those with unilateral hypertension, is to do two blood tests, to sort out the adenomas, using iodocholesterol scans before and underlying cause of the hypertension. Here I speak not of a diagnostic rubric, but of the physiological astonishment, by 1983 we had studied 100 such drivers of the hypertension. From the over 10,000 patients, and not a single one had a hot unilateral adult patients I have seen with resistant adrenal gland: all but a few (presumably patients hypertension, only 9 were due to licorice, only 3 with unrecognized Liddle’s syndrome or variants) were due to coarctation of the aorta, and only 51 had hot adrenal glands bilaterally, and about 30% were due to pheochromocytoma. The vast majority suppressed with dexamethasone. When Biglieri were due to disorders of the powerful feedback loop described his first four cases of idiopathic primary that regulates salt and water retention: the hyperaldosteronism due to bilateral adrenocortical hyperplasia in 198515, we had already subjected 10 such patients to adrenalectomy because they could Table 1. Some causes of low-renin hypertension
not be controlled medically; all had bilateral adrenocortical hyperplasia. Of these 4 had African Apparent minerallocorticoid excess30
ancestors; one was a visiting clergyman from -Licorice
Africa; the others were from North Buxton. At least Conn’s syndrome?*
one had a 1.5 cm nodule that could easily have been Primary adrenocortical hyperplasia15
mistaken for a Conn’s tumor. Our subsequent Adrenal enzyme deficiencies
experience has been that, knowing the diagnosis, -11beta-Hydroxylase, 17 alpha-hydroxylase
most such patients can be controlled medically; deficiency31
Dexamethasone-suppressible hypertension
-chimaeric aldosterone synthase gene32, 33
Gordon’s syndrome 34
hypertension accounts for an important proportion Liddle’s syndrome and variants19, 20, 35, 36:
of resistant hypertension, in hypertension clinics -renal tubular Na channel abnormality;
around the world. Eide et al16, in Norway, found GIP dependent cortisol excess with nodular
that two thirds of patients with resistant hyperplasia37
hypertension had low-renin status. Gallay et al., in * it seems likely that many, if not all cases of California, reported that among patients with “Conn’s syndrome”, represent nodules in patients resistant hypertension, 17% had an elevated ratio of aldosterone to renin17. Ouzan et al18, in France, found that the addition of spironolactone controlled By measuring plasma renin and aldosterone, blood pressure in 92% of patients with resistant patients can be divided into three categories, each hypertension. Baker et al19 reported in 2002 that in requiring different medical therapies. Table 1 lists London, UK, 5% of hypertension in black patients some of the causes of low-renin hypertension. (mainly of Afro-Caribbean origin) was due to a Table 2 outlines an algorithm for individualizing polymorphism of renal epithelial sodium channels, therapy of hypertension, based on levels of plasma i.e. a variant of Liddle’s syndrome, with a specific
Table 2. Individualized therapy for hypertension

Liddle’s syndrome and
Renal or renovascular
variants, or

Low Low High
Aldosterone High
Primary treatment
Amiloride Angiotensin
spironolactone or
(Rarely decompression
or revascularization)
(Rarely surgical)
* amiloride for men, where eplerenone is not available

Patients with low renin and high aldosterone have
primary hyperaldosteronism, which is almost been trying to tell us is that there is no single “best always due to bilateral hyperplasia, and the primary therapy” for all patients with hypertension: what treatment is with aldosterone antagonists. Where physicians need to do is to define the underlying eplerenone is not available for men (because of cause of the hypertension in each patient, and gynecomastia from spironolactone), amiloride in individualize the therapy for that patient. Doing so high doses (80mg/day or more) may be used. Such has tremendous potential for reducing the burden of doses would never be used in the absence of a cardiovascular disease, particularly of stroke25, and diagnosis, but may be necessary for medical control particularly among African-Americans in the US in such patients. If the renin is low and the Stroke Belt26, and perhaps among Africans. aldosterone is low, the problem is a variant of Effective blood pressure control has the potential to Liddle’s syndrome, or minerallocorticoid excess, reduce stroke by half25; the types of stroke that are prevented are lacunar infarctions, and intracerebral (Triamterene is problematic because of casts and hemorrhages, both due to hypertensive small vessel interstitial nephritis 23.) If the renin and disease. In the North American Symptomatic aldosterone levels are both high, the problem is Carotid Endarterectomy Trial, we reduced secondary hyperaldosteronism, due to a renal or intracranial hemorrhage to 0.4% of stroke27, and this renovascular problem. (Not uncommonly this may included subarachnoid hemorrhages, which are not be due to renal microvascular disease secondary to caused by hypertension. It is long past time that hypertension itself; I call this “tertiary clinical trials of this strategy, which has the hypertension”.) In this setting the primary potential to improve the cost-utility of therapy for treatment is angiotensin receptor blockers; in some hypertension by about two thirds28, be carried out. cases patients with obstruction may require A straightforward approach would be to randomize decompression of the urinary tract, and patients Hypertension Clinics in the Stroke Belt, and/or in with true renovascular hypertension may require Africa, to usual care vs. individualized therapy for revascularization24. The most difficult patients are hypertension based on aldosterone:renin ratios, using a cluster randomization design29. Data hypertension: I have seen a dozen who began with needed to calculate cost-utility should be collected. primary hyperaldosteronism, and went on to develop renovascular hypertension; such patients may need both aldosterone antagonists and angiotensin-receptor blockers, a combination that References
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