The ‘pyrrhic victory’ of amlodipine over hydrochlorothiazide in the OLAS Study

Abstract

We read with interest the well-written article by Martinez-Martin et al. 1 entitled 'olmesartan/ amlodipine versus olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS Study'. The authors by using a parallel group, prospective open-label, blinded end-point design, have elegantly shown that both olmesartan combinations were well tolerated, effective in reducing blood pressure and additionally demonstrated benefit for different cardiorenal risk markers. Moreover, amlodipine (5-10 mg per day) confirmed its reputation as a metabolically neutral drug with beneficial effects on the inflammatory milieu as compared with hydrochlorothiazide (12.5-25 mg per day).However, there are several points not addressed by the presentation of the OLAS Study, thus generating some concerns. First, no lifestyle interventions were implemented in that group of high-cardiovascularrisk patients. Interestingly, both body mass index and waist circumference were almost similar between baseline and after 78 weeks of follow-up. The latter phenomenon explains per se that the main component of metabolic syndrome, namely, increased central adiposity, remained unchanged even in the context of the ameliorated metabolic disorder; inflammatory; and hemodynamic pattern resulted from the ongoing amlodipine-oriented therapy. Second, it is known that patients with metabolic syndrome are characterized by impaired sodium handling and nocturnal hypertension, two mechanisms explaining at least partly the pathophysiological pathways of the hypertensive status. 2 No measure for these situations is delivered by the design of the OLAS Study (that is, 24-h sodium excretion and blood pressure measurement), thus creating some queries for both the salt-sensitivity status and the overall hemodynamic load of the studied population. Third, it is ignored that metabolic-syndrome patients frequently experience sleep apnoea syndrome, which constitutes an outstanding confounder for the investigated outcomes. 3,4 Finally, with respect to the timing of drug administration, it is not reported whether office blood pressure measurements were performed before the delivery of the morning pill or whether that issue was completely ignored in the investigational pathway. In the same lines, in our view, morning blood pressure measurements were performed in a very large interval (from 0830 to 1130 hours) of time.The hard end-points assessment from the AC-COMPLISH and ALLHAT, taken together, suggest that p25 mg of hydrochlorothiazide are less protective either than full doses of amlodipine or appropriate doses of other diuretics used elsewhere. 5 The OLAS Study extends the previous experience from large trials to intermediate end points of cardiovascular risk. However, we additionally feel that the OLAS Study confirms with clarity the 'hypertension paradox', 6 and clinical efforts should point out to reverse that phenomenon by aggressively implementing lifestyle interventions at the first line of management of high-cardiovascular-risk patients, as sug...

The ‘pyrrhic victory’ of amlodipine over hydrochlorothiazide in the OLAS study: response from the authors

“…As Thomopoulos et al 3 point out, no reduction in body mass index or waist circumference was achieved in our study. It cannot be concluded, though, that the overall cardiovascular risk of our patients was not reduced, as large reductions in blood pressure and albuminuria were attained in both treatment arms.…”

“…Thomopoulos et al 3 also refer to some possible confounders, such as the circadian blood pressure rhythm, the sleep apnea syndrome, the 24-h sodium excretions and the timing of the blood pressure measurements. In a subset of the patients of the ACCOMPLISH trial, 6 ambulatory monitoring of blood pressure was performed and no differences could be found between the treatment arms, supporting the interpretation that the observed difference in cardiovascular outcomes was not caused by differences in blood pressure, but by intrinsic properties of the studied combination therapies.…”

“…Remarks by Thomopoulos et al 3 remind us that lifestyle counseling is all too often the Cinderella of hypertension management, 8 and that weight loss should be more aggressively pursued in high-risk patients with metabolic syndrome.…”

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“…Equally not yet well understood is the mechanism by which hydrochlorothiazide interferes with the glucose homeostasis [12][13][14]. There is also a whole range of side effects, fortunately rarer, but described in the medical literature, ranging from the appearance of lupus [15], interstitial lung disease [16], even severe allergic states [17], pulmonary edema [18][19][20], all conditions linked to immunological changes induced by the molecule itself.…”