The major results from this investigation demonstrate that six months of treatment with either HCTZ or the mineralocorticoid antagonist SPIRO resulted in comparable lowering of 24-hr average and nocturnal BP in an older hypertensive patient population. At the 6-month time period the 24-hr average and nocturnal SBP were significantly lower among the SPIRO treated group. In addition, HCTZ and SPIRO treatments were associated with comparable benefits in reducing pulse pressure and pulse wave velocity, suggesting a reduction in vascular stiffness. There were no significant adverse events and both drugs were well tolerated.
Developed more than 50 years ago, SPIRO has been primarily used as a potassium sparing diuretic in volume overload states such as congestive heart failure and cirrhosis and to treat primary hyperaldosteronism (7
). Several early studies demonstrated its effectiveness as a single agent in treating essential hypertension (8
). More recently, randomized controlled trials have demonstrated that mineralocorticoid antagonists reduced cardiovascular events and improved morbidity and mortality in patients with severe heart failure and in patients following myocardial infarction (10
). These studies emphasized the importance of “aldosterone escape” during ACE inhibitor therapy and led to a reexamination of aldosterone’s vascular effects. In addition, local, vascular, production of aldosterone has been identified to contribute to vascular stiffness and myocardial fibrosis.
Aldosterone antagonists antagonize the aldosterone-induced upregulation of the angiotensin receptor 1, ACE activity and stimulation of vascular smooth muscle cell growth which may contribute to a decrease in vascular stiffness (12
). Given these actions of aldosterone and its potential contribution to the development of vascular stiffness – the major pathophysiologic characteristic of geriatric hypertension – the effect of treatment with the mineralocorticoid antagonist SPIRO on two measures of arterial stiffness is of clinical importance. Significant reductions in pulse pressure and in PWV were identified with SPIRO treatment that were comparable to the reductions achieved with HCTZ treatment. Only one prior study has assessed vascular stiffness outcomes following treatment with the aldosterone antagonist eplerenone (13
). This 24-week study also identified a reduction in PWV.
Current guidelines for the pharmacological management of hypertension in older patients recommend thiazide type diuretics for most patients (14
). Many randomized trials have shown thiazide diuretics to be equally efficacious in reducing the incidence of cardiovascular events in comparison to the other antihypertensive drug classes (15
). However, thiazide diuretics carry a risk for potentially undesirable metabolic side effects such as hypokalemia, hypertriglyceridemia, impaired glucose tolerance and increases in serum cholesterol and uric acid (16
). By comparison, despite clinical trial data showing that both selective and non-selective aldosterone antagonists are effective as monotherapy in treating hypertension, these agents have received less attention as alternative therapies (8
). As a class, these agents antagonize aldosterone’s effect to increase renal sodium reabsorption, alter renal hemodynamics, increase afterload and increase vascular stiffness (2
The effect of thiazide diuretics to reduce SBP to a greater extent than DBP and lead to a reduction in PP is a feature that is well tailored to the treatment older hypertensive patients. The comparable reduction in pulse pressure noted between HCTZ and SPIRO is clinically important due to concerns about potential harmful effects resulting from excessive reductions in diastolic blood pressure (the J-curve phenomenon) that may occur during treatment of primarily systolic hypertension. Both HCTZ and SPIRO treatment led to larger reductions in SBP relative to DBP and consequently statistically significant reductions in pulse pressure.
The results from the present study demonstrate that HCTZ treatment is associated with a significant reduction in PWV, independent from its BP lowering effect (). Previous studies comparing thiazide diuretics to other antihypertensives have not demonstrated a reduction in PWV or other measures of vascular stiffness in association with thiazide diuretic therapy (17
). These studies were of much shorter duration (4 weeks) and therefore may not have allowed for the chronic effects of thiazides to become evident.
Since there were comparable reductions in pulse pressure and PWV in the HCTZ and SPIRO treatment groups, it is possible that the reduction in vascular stiffness was primarily due to the decrease in blood pressure per se
. The lack of a significant overall relationship between the change in PWV and the change in SBP () argues against this possibility – certainly in the HCTZ treated group. In contrast to the HCTZ treated group, there was a trend for a direct association between the change in PWV and the change in SBP among the SPIRO treated group. Finally, it is important to point out that prior studies have not identified treatment-associated reductions in PWV despite significant reductions in BP across several classes of antihypertensive drugs. For example, a 10-week study of perindopril, atenolol, lercanidipine and bendrofluazide found no effect on PWV with any of these drugs (18
It has been demonstrated that lower PWV is associated with lower overall cardiovascular risk even after the confounding effects of pulse pressure and blood pressure level are taken into account (19
). The age-related change in PWV has been estimated to increase by 1.36 m/sec per decade (21
). Thus, the magnitude of the decrease in PWV noted in each treatment group – approximately 1 m/sec – is likely to be clinically relevant.
Several studies have demonstrated the advantages of 24-hr ambulatory blood pressure monitoring over office determinations with regard to CV risk prediction (22
). In particular, nocturnal BP and dipping patterns have been reported to be the best predictors of risk, independent of the average 24-hour blood pressure (25
). It is thus important to have demonstrated comparable BP lowering effects of SPIRO to HCTZ across the entire 24-hour period. Based on the diurnal variation of aldosterone levels which are known to be higher in the late evening and into the early morning hours, it was thought that SPIRO treatment may exert an enhanced reduction in nocturnal BP relative to treatment with HCTZ. While a reduction in nocturnal BP was identified in both HCTZ and SPIRO groups, nocturnal SBP was significantly less in SPIRO compared with the HCTZ group at the 6-month time point.
Several limitations inherent in this study’s design deserve comment. The subject population recruited for this investigation was selected to represent a geriatric population with simple hypertension. The 4-week antihypertensive drug withdrawal period was believed to be an important design element to avoid confounding effects of antihypertensive therapy on physiologic measures taken at baseline, but this restricts the study findings to individuals with mild hypertension who are able to tolerate this withdrawal period. Therefore these results may not generalize to older patients with more severe hypertension or those with common co-morbid conditions such as diabetes. The relatively small sample size of this study also imposes limits on its generalizability. In addition, the six-month study duration does not permit extrapolation of these findings to longer term therapy.
In conclusion, in older hypertensive patients, 6 month treatment with SPIRO was demonstrated to be associated with significant reductions in average 24-hr and nocturnal SBP and DBP and measures of vascular stiffness – pulse pressure and PWV – comparable to the reductions in these outcomes in subjects randomized to HCTZ therapy. With recent data revealing potentially important beneficial metabolic effects of mineralocorticoid blockade, the potential physiological and longer term clinical benefits of mineralocorticoid antagonist therapy in this hypertensive patient population should be further investigated.