Resistant hypertension and aldosterone excess: new insights from ambulatory blood pressure monitoring

Introduction Although representing a major goal of antihypertensive treatment, blood pressure control is far from being achieved in current clinical practice [1]. Epidemiological surveys carried out in different parts of the world have shown that no more than 25–29% of treated hypertensives display blood pressure values ≤140/90 mmHg [1]. The situation has been shown to be not so much different in clinical trials, in which patients' and doctors' motivation to reduce blood pressure at goal is greater than that usually displayed in daily clinical practice [2]. In addition, data collected in the context of a subproject of the European Lacidipine Study on Atherosclerosis (ELSA) have recently shown that not only is it difficult to achieve blood pressure control, but also it is problematic to maintain it throughout time [3]. Finally, a further element that makes the whole matter even more complex refers to the evidence that an uncontrolled home and/or ambulatory blood pressure carries a risk for cardiovascular morbidity and mortality similar to (and in some instances even greater than) that found for sphygmomanometric blood pressure [4]. Resistant hypertension Resistant hypertension, that is the condition defined by the 2007 European Society of Hypertension/European Society of Cardiology guidelines [5] as the clinical state in which ‘a therapeutic plan that has included attention to lifestyle measures and the prescription of at least three drugs in adequate doses has failed to lower systolic and diastolic blood pressure at goal’, is one of the most frequent causes of poor blood pressure control. The prevalence of refractory hypertension clearly depends on the clinical setting, but is said to be around 5–18% [6]. Teaching used to focus on undiagnosed secondary hypertension as a cause of refractory hypertension, but factors in the patient–doctor interaction are increasingly recognized as important. In a tertiary referral clinic for refractory or resistant hypertension (the terms are used inter-changeably) secondary hypertension was responsible for only 11% of cases, whereas two-thirds were due to inadequate therapy, either due to a suboptimal medical regime (43%), medication intolerance (14%) or non-compliance (10%) [7]. The other key factors are volume overload (due to excess salt intake, renal disease or inadequate diuretic therapy) and lifestyle features (i.e. alcohol abuse, obesity, hypertensinogenic drugs). Management of patients with refractory hypertension may involve optimizing therapy, lifestyle changes, increasing drug dosage and/or frequency, use of synergistic drug combinations and the addition of diuretics and/or aldosterone antagonists. Aldosterone antagonism Aldosterone antagonists have been known to be effective in hypertension for nearly half a century [8] and also have been suggested in refractory hypertension for decades [9], but until recently they have not been used widely or recommended in standard medical texts. Over the past 5 years there has been increasing interest in the role of aldosterone antagonists, most particularly spironolactone, in patients with refractory hypertension [10–13]. Calhoun and colleagues from Birmingham, Alabama have reported on the efficacy of low-dose spironolactone in these patients [14]. The very interesting study in this issue of the Journal of Hypertension by Pimenta et al. from the Birmingham laboratory [15] provides an underpinning pathophysiological rationale for the success of aldosterone antagonists in this context, using 24-h ambulatory blood pressure monitoring. Study's strengths and limitations The study has a number of strengths. These include its prospective nature, the use of 24-h blood pressure monitoring as well as office blood pressure measurements, the measurement of integrated aldosterone excretion over 24 h, and the relatively large numbers of patients enrolled in the study. The study does, however, have some weaknesses, as acknowledged by the authors. They have chosen to conduct an observational study, and used uncorrected statistics, so the study can only be regarded as hypothesis generating and requires verification using more rigorous approaches. The fact that, understandably, many patients were on ongoing antihypertensive therapy raises some questions around interpretation of renin measurements, although this evaluation appears to be less problematic in relation to aldosterone. The classification into high and low aldosterone is somewhat arbitrary: hypertension research is bedevilled by use of dichotomies, hypertension itself being the prime example, given the continuous nature of blood pressure distribution. A particular problem, in the context of refractory hypertension, is the failure of the authors to use urinalysis to exclude primary renal disease. ‘Essential’ hypertension may be misdiagnosed without examination of the urine [16]. At least, urinalysis should be used to exclude haematuria and proteinuria, as renal impairment is by no means invariable in early primary renal disease. In a German study of patients with glomerulonephritis, the frequency of hypertension was 34% in patients with normal serum creatinine [17]. A Danish study also showed that glomerulonephritis is associated with a high rate of hypertension, even before renal insufficiency has developed [18]. Thus, in the absence of a negative urinalysis and urine microscopy, it is difficult to exclude primary renal disease categorically, by far the most common cause of secondary hypertension and an important cause of refractory hypertension. In summary, this is an interesting study suggesting that high aldosterone levels might impart increased cardiovascular risk and providing a scientific rationale for use of aldosterone antagonists in refractory hypertension, but the hypothesis requires further testing.