The influence of cardiovascular and antiinflammatory drugs on thiazide-induced hemodynamic and saluretic effects

Objective Thiazide diuretics are known to induce a transient fall of the glomerular filtration rate (GFR), which, in turn, reduces tubular Na⁺ load. This tubuloglomerular feedback (TGF) curtails the natriuretic effect of this class of diuretics. Cardiovascular and antiinflammatory therapeutics may interfere with TGF and thereby influence the effect of thiazides once co-administration is clinically indicated. Methods The effects on GFR and saluresis of hydrochlorothiazide (HCT; 25 mg) monotherapy were measured in healthy volunteers and compared to those obtained during co-administration of the thiazide and a second therapeutic.Results In the presence of the ACE inhibitor enalapril (10 mg), the transient fall in the GFR induced by HCT was almost abolished, and Na⁺ excretion increased by ∼30 % as compared to HCT monotherapy. K⁺ excretion, however, remained unchanged. Similar results were obtained with the AT II type 1 receptor antagonist candesartan (8 mg): GFR remained stable, Na⁺ excretion rose by 35 % and K⁺ excretion was not changed. The effect of the Ca²⁺ channel blocker amlodipine (5 mg) on GFR and HCT-induced Na⁺ excretion equalled that obtained with the AT₁ blocker, yet with this treatment K⁺ excretion rose in proportion to Na⁺ excretion. The β-blockers propranolol (80 mg) or bisoprolol (5 mg) reduced GFR but maintained TGF. HCT-induced Na⁺ excretion was significantly reduced in the presence of a β-blocker, whereas K⁺ excretion was not changed. The inhibition of cyclooxygenase by diclofenac (50 mg) or rofecoxib (25 mg) significantly reduced the diuretic/natriuretic effect of HCT, but K⁺ excretion was unchanged, and TGF was still demonstrable. Conclusion In conclusion, AT₁ receptors, as well as the Ca²⁺ channels in the smooth muscle cells of the afferent arteriole, are considered prerequisites for TGF function; their blockade increases the diuretic/natriuretic efficacy of thiazide diuretics. In contrast, β-blockers and COX inhibitors do not interfere directly with TGF. These first dose effects reflect the primary response of the kidney to the drugs. They cannot, however, predict the benefits of long-term treatment.     

Torasemide significantly reduces thiazide-induced potassium and magnesium loss despite supra-additive natriuresis

Background  Resistance to high-dose loop diuretics can be overcome either by co-administration with thiazides or by treatment with medium-dose loop diuretics combined with thiazides. Combination therapy has been proven to be superior to high-dose loop diuretic monotherapy for cardiac and renal edema. However, such a strongly efficacious short-term regimen is often complicated by undesired effects, including circulatory collapse and electrolyte disturbances. The question of whether the loop diuretic/thiazide combinations are efficacious and safe when conventional doses are combined has not yet been answered. Methods  The effects of hydrochlorothiazide (HCT) and torasemide (TO) given alone on the excretion of Na⁺, Cl^-, K⁺, Mg²⁺, and Ca²⁺ were compared with the effects of combined administration of the diuretics in 12 healthy volunteers. Results  The co-administration of HCT (25 mg) with TO (5 or 10 mg) strongly increased Na⁺ excretion. However, the combination significantly reduced K⁺ and Mg²⁺ excretion. The K⁺-sparing effect of the HCT/TO combination was shown to be due to a significant reduction in the HCT-induced increase in fractional K⁺ excretion by the loop diuretic. Total excretion of Ca²⁺ relative to Na⁺ excretion was less with the HCT/TO combination than with TO given alone. Conclusion  The enhancement of desired NaCl excretion by the HCT/TO combination with significant reduction of undesired loss of K⁺ and Mg²⁺ meets clinical requirements but has to be validated in long-term clinical trials.     

On the pharmacological actions of a diuretic,fenquizone, with particular reference to its site of action

The pharmacological actions of a diuretic drug, fenquizone have been investigated and its effects compared with well characterized diuretics in rats, mice and rabbits. Changes in sodium and potassium excretion and urine volume were similar in magnitude and duration to those of the thiazide diuretics over dose range 0·05–100 mg kg^?1. Free water clearance in rabbits was decreased indicating an action at the cortical diluting site in the nephron and since free water reabsorption was relatively unaffected it appears unlikely to have actions at other sites. Calcium and phosphate excretion studies also suggested that the predominant effects are those occurring at the cortical diluting segment of the nephron. Additional parameters not affected by the drug were blood flow to the cortex and medulla of the kidney (and other major organs), plasma glucose concentration and plasma urate concentration.     

The effects of midodrine on the natriuretic response to furosemide in cirrhotics with ascites

Aliment Pharmacol Ther 2010; 32: 1044–1050

Summary

Background Resistance to loop diuretics is common in patients with ascites. Diminished glomerular filtration rate (GFR) is thought to mediate resistance to loop diuretics. Midodrine, a commonly used alpha‐1 agonist, has been shown to improve GFR in non‐azotemic patients with cirrhosis. Aim To conduct a randomized, double‐blind, placebo‐controlled, cross‐over study to test the hypothesis that midodrine significantly increases natriuretic response of IV furosemide in non‐azotemic cirrhotics with ascites. Methods All subjects participated in both phases, which were (i) furosemide IV infusion + oral midodrine 15 mg administered 30 min before furosemide (ii) furosemide IV infusion + oral placebo administered 30 min before furosemide. Primary outcomes were 6‐h urine sodium excretion and 6‐h total urine volume. Results A total of 15 patients (men: 8; age: 52.7 ± 7.6 years; serum creatinine: 1.06 ± 0.2 mg/dL) were studied. Total 6‐h urine sodium excretion was 109 ± 42 mmol in the furosemide + midodrine treatment phase and was not significantly different from that in the furosemide + placebo treatment phase (126 ± 69 mmol, P = 0.6). Similarly, mean 6‐h total urine volume was not significantly different between two groups (1770 ± 262 mL vs. 1962 ± 170 mL, P = 0.25). Conclusions Oral midodrine does not increase the natriuretic response to furosemide in non‐azotemic cirrhotic patients with ascites. Orally administered midodrine does not increase natriuretic response to furosemide in non‐azotemic cirrhotic patients with ascites.     

Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives

Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.     

The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man.

We have studied the effect of a single dose challenge of naproxen (500 mg) and sulindac (200 mg) on renal function in five volunteers, and the effect of a single dose challenge of the thiazide, hydrochlorothiazide (100 mg), and loop diuretic, piretanide (6 mg) on renal function when the diuretics were given alone or when superimposed on chronic therapy of either naproxen or sulindac. None of the nonsteroidal anti-inflammatory drug (NSAID) or diuretic exposures significantly influenced glomerular filtration rate, as measured by creatinine clearance. Over the first 4 h of the study, both naproxen and sulindac reduced fractional excretion of sodium by approximately 50%. Sulindac also caused a significant uricosuria whilst naproxen promoted urate retention. Similar changes were observed over 8 h. Superimposition of either hydrochlorothiazide or piretanide on top of chronic sulindac therapy resulted in a blunting of the natriuresis by approximately 30% compared to when these diuretics were given alone: the action of the diuretics was unchanged by naproxen. Sulindac pretreatment did not alter the urinary excretion of either hydrochlorothiazide or piretanide; naproxen did not alter hydrochlorothiazide excretion. On the basis of these findings, it is concluded that NSAIDs exert direct tubular effects that do not necessarily interfere with the delivery of diuretics to their sites of action within the nephron.     

Clinical trial: short‐term effects of combination of satavaptan,a selective vasopressin V2 receptor antagonist,and diuretics on ascites in patients with cirrhosis without hyponatraemia – a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 834–845

Summary

Background There is little information on the effects of vaptans in patients with cirrhosis. Aim To investigate the short‐term effects of satavaptan, a selective vasopressin V₂ receptor antagonist on ascites in cirrhosis without hyponatraemia. Methods A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double‐blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day. Results Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was ?0.36 kg (±3.03) for placebo vs. ?2.46 kg (±3.11), ?2.08 kg (±4.17) and ?2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar. Conclusions The administration satavaptan for a 14‐day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

     

Piretanide: a loop-active diuretic. Pharmacology, therapeutic efficacy and adverse effects

Piretanide is a high-ceiling, loop-active diuretic that has been developed for treatment of congestive heart failure, hypertension and edematous states caused by renal and hepatic diseases. Piretanide is structurally related to furosemide and bumetanide; when administered orally, 6 mg of piretanide is as effective as 40 mg of furosemide, and when administered intravenously, 12 mg of piretanide is as effective as 40 mg of furosemide. Piretanide enhances water and sodium excretion in patients with congestive heart failure, with nephrotic syndrome and with cirrhosis and ascites. Adverse effects reported to date are limited to those attributable to excess loss of fluid and electrolytes. Under some conditions, piretanide appears to be less potassium wasting than thiazide diuretics or other loop-active diuretics.     

Hydrochlorothiazide versus spironolactone: long-term metabolic modifications in patients with essential hypertension

The metabolic side effects of thiazide diuretics are believed to be responsible for the failure of thiazide diuretics to reduce cardiovascular morbidity in patients with hypertension. However, the decrease in the incidence of osteoporotic fractures that are associated with thiazide administration may be relevant in elderly patients with arterial hypertension. Spironolactone (SP) appears not to influence the metabolic risk profile of the patient with hypertension, and no studies have examined its effect on calcium metabolism. Therefore, in 22 patients with mild to moderate essential hypertension, the authors performed a parallel, randomized, double-blind, placebo-controlled study that compared the effects on serum urate and lipid, potassium, magnesium, and calcium metabolism of hydrochlorothiazide (HC) (mean [+/- SD] dose, 72 +/- 26 mg/d) and SP (144 +/- 53 mg/d) during a 52-week period. As compared with placebo, HC significantly increased serum urate and total cholesterol concentrations, and decreased serum potassium levels. SP did not affect serum urate or cholesterol levels but increased serum potassium concentrations. Neither diuretic significantly modified magnesium metabolism. Little changes were seen in serum calcium levels during HC or SP treatment, whereas urinary calcium excretion was significantly decreased by HC (mean decrease, 45%; P less than .01) or SP (40%; P less than .01). The authors conclude that SP, in addition to its potassium-sparing properties, has a calcium-sparing effect that may be beneficial for patients in whom reduction of urinary calcium excretion has a therapeutic value.     

Mechanism of action of xipamide and its classification as a "low ceiling diuretic". Pharmacodynamic-pharmacokinetic studies in healthy volunteers and in kidney and liver patients

Xipamide (CAS 14293-44-8) shows structural features comparable with the thiazide- as well as the class of loop diuretics. According to earlier findings this diuretic, in contrast to the thiazides, should not decrease the glomerular filtration rate (GFR) and be effective even in patients with advanced renal failure. Therefore recently the question, which class of diuretics xipamide should be related to, has been increasingly discussed. In order to solve this issue, the diuretic effect of xipamide was assessed in healthy volunteers once without and once under strict water and salt restriction. Additionally, changes in GFR were monitored by means of measurement of the creatinine clearance. Kinetic parameters were determined in plasma and urine; further, in patients with liver cirrhosis, renal elimination kinetics of the diuretic were correlated with the concentration of direct plasma bilirubin, as a marker of cholestasis, at the beginning of a treatment with xipamide, 40 mg qd. The investigations proved that xipamide, like a typical thiazide diuretic, gives rise to a temporary decrease in GFR of about 30 %, provided the renin-angiotensin-aldosterone system of the volunteer is activated by previous salt and water restriction. Xipamide leads to an increase of K+ and Mg2+ excretion, but to a decrease of Ca2+ excretion in urine, a charactaristical feature of the thiazide-like diuretics. The correlation between Na+ excretion and drug excreted in urine over time showed a functional graph that is characteristic for a "low ceiling" thiazide diuretic. In patients with renal failure FE(Na) was increased when related to the GFR-adjusted drug excretion rate, whereas it was diminished in conditions with decreased effective circulating volume like in liver cirrhosis with ascites. It could be shown that the elimination kinetics of xipamide are determined by renal drug clearance, which proportionally decreases with GFR. In patients with liver failure, a decrease of non-renal drug clearance went along with an increase in urinary drug excretion. The amount of drug excreted in urine (Ae) proportionally increased with the concentration of the patients' direct plasma bilirubin. Thus, from a pharmacological as well as clinical point of view xipamide acts like a thiazide diuretic. As could be shown for other thiazides some time ago, xipamide is effective not only in patients with cardiovascular diseases, but also in those with advanced renal failure.     

Enalapril and hydrochlorothiazide in hypertensive Africans

Summary The antihypertensive efficacy both of angiotensin converting enzyme (ACE) inhibitors and thiazide diuretics has been claimed to be influenced by plasma renin activity, which declines with age and is low in blacks. In a double-blind, placebo-controlled, double-dummy, randomized, parallel-group preliminary study, the antihypertensive efficacy and tolerability of the ACE inhibitor enalapril (20 mg day^–1) and hydrochlorothiazide (50 mg day^–1) were evaluated and compared for 4 weeks in 20 African patients with essential hypertension. The two groups had similar baseline clinical features and serum Na⁺ and K⁺ levels.Hydrochlorothiazide caused a significant and sustained fall in erect blood pressure with a reflex tachycardia. Enalapril exerted only a modest antihypertensive action, but significantly reduced erect heart rate.Direct comparison of hydrochlorothiazide — and enalapril — induced hypotension suggested a greater fall in subjects on the thiazide. The 95% confidence limits for the thiazide-enalapril difference in antihypertensive action at the end of the study was 39.5 to –7.5 mm Hg systolic and 22.0 to –6.6 mm Hg diastolic. The maximal blood pressure fall after hydrochlorothiazide was positively correlated with age (r=0.50;p<0.05), whilst that of enalapril was inversely related age to (r=–0.57,p<0.05).The results are compatible with the notion that ACE inhibitor monotherapy may be less effective than thiazide diuretic treatment in African and black patients with essential hypertension. The findings also support the concept that age and racial factors may influence the response to antihypertensive treatment.     

Effect of angiotensin-converting enzyme insertion/deletion genotype on collagen type I synthesis and degradation in patients with atrial fibrillation and arterial hypertension

Objective: The present study was undertaken to assess the impact of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphisms on circulating markers of collagen type I synthesis and degradation, and also to study the effect of therapy with ACE inhibitors on these markers in hypertensive patients with atrial fibrillation (AF). Research design and methods: ACE I/D genotypes were assessed in 158 hypertensive patients (71 ± 9 years; 72 male) with AF and 174 patients with arterial hypertension in sinus rhythm (SR) (71 ± 9 years; 88 male). Serum concentrations of amino-terminal propeptide of pro-collagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were measured. Results: Of the 332 study participants, 74 (22.3%) were I/I, 158 (47.6%) were I/D and 100 (30.1%) were D/D carriers. Genetic variation in ACE significantly influenced serum CITP levels in AF patients (p = 0.011). CITP levels were lower in D allele carriers (DD and ID) compared with I/I carriers. There was no difference in PINP levels between the different ACE genotype groups (p = 0.302). Patients treated with ACE inhibitors had higher CITP levels compared with those not treated (p = 0.036). Conclusions: This study suggests that the presence of the D allele in hypertensive patients with AF is associated with attenuation of type-I collagen degradation, and that therapy with ACE inhibitors increases degradation of collagen type I. The data indicate a subgroup of patients with AF and arterial hypertension who may benefit to a greater extent from therapy with ACE inhibitors, thus, providing a basis for pharmacogenetics.     

Pharmacodynamics and pharmacokinetics of xipamide in patients with normal and impaired kidney function

Summary The effect of a single oral dose of 40 mg xipamide on urinary excretion of Na⁺, K⁺, Cl^–, Ca²⁺ and Mg²⁺ in healthy subjects and in patients with varying degrees of renal impairment was compared with various conventional diuretics. Xipamide caused marked excretion of Na⁺ and Cl^–, whereas the diuretic produced only moderate kaliuresis; urinary excretion of Ca²⁺ was increased in proportion to Na⁺, like the loop diuretics. Xipamide affected electrolyte excretion even in patients with a creatinine clearance below 30 ml/min, as do the loop diuretics, too. Therefore, the pharmacodynamic characteristics of xipamide are more like those of a loop diuretic than of a thiazide. Xipamide was good bioavailable, its t_1/2 was 7 h and urinary recovery of the undegraded drug was 40% of the given dose. In renal insufficiency, t_1/2 increased from 7 to only 9 h, yielding a moderate increase in the AUC. Urinary recovery of the drug was reduced in proportion to the reduction in the creatinine clearance of the patient. Therefore, significant extrarenal elimination of the diuretic must be postulated, which suffices to prevent significant drug accumulation in renal failure.     

A comparative study of the action of frusemide and methyclothiazide on renin release by rat kidney slices and the interaction with indomethacin.

1 The effects of frusemide (a diuretic acting on the loop of Henle) and methyclothiazide (a thiazide diuretic) on renin release were studied on rat kidney slices. 2 Frusemide at concentrations of 1.5 and 7.5 mmol/l produced significant increases in renin release but had no effect at 0.15 mmol/l. 3 Methyclothiazide in a similar concentration range did not increase renin release; instead, at the highest concentration used, methyclothiazide (3.5 mmol/l) inhibited renin release. 4 Indomethacin (25 mumol/l) did not inhibit the increase of renin induced by frusemide. 5 Our limited study in vitro is consistent with the findings of other workers who have shown in vivo, in the absence of systemic electrolyte depletion, that only "loop diuretics" increase renin secretion. Under our experimental conditions, it is suggested that frusemide exerts a direct action either upon the epithelioid cells or upon the macula densa since the renal prostaglandin system does not intervene.     

Significance of the calcium to creatinine concentration ratio of a single-voided urine specimen in patients with hypercalciuric urolithiasis

Thirty-six patients with recurrent calcium oxalate nephrolithiasis were selected from the stone clinic. Fourteen were normocalcemic and had normal daily urinary calcium excretion. Among 22 patients with idiopathic hypercalciuria, 10 received thiazide diuretics for the prevention of new stone formation. Single-voided urine samples were collected at the outpatient clinic and 24-hour urine at the patients' homes. In hypercalciuric patients, irrespective of thiazide diuretic therapy, the mean value of the calcium/creatinine concentration ratios of postprandial single-voided urine specimens had a meaningful correlation with the man value of 24-hour urinary calcium excretion rates. Also in hypercalciuric patients with thiazide diuretics, a negative correlation was observed between the calcium/creatinine concentration ratio and the index for urinary saturation with calcium oxalate of a postprandial single-voided urine sample. Thus, in the hypercalciuric stone formers, 24-hour urinary calcium excretion rates and the degree of urinary saturation with calcium oxalate can be estimated from the calcium/creatinine concentration ratios of single-voided urinary samples.     

Bioavailability of bemetizide and triamterene from a combination formulation

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (P < 0.01) from that from a tablet containing 25mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3ngml^?1) was lower than that after administration of bemetizide alone (87.9 ngml^?1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml^?1) was higher than and significantly different (p< 0.001) from that after administration of triamterene alone (15.7 ng ml^?1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post-dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post-dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data. The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.     

Comparison of natriuretic, uricosuric, and antihypertensive properties of tienilic acid, bendrofluazide, and spironolactone.

The antihypertensive properties of the new diuretic tienilic acid were investigated. Thirteen previously untreated hypertensive patients took part in a double-blind crossover study in which 30 days' treatment with tienilic acid 250 mg, bendrofluazide 5 mg, and spironolactone 100 mg were compared. Bendrofluazide caused the greatest natriuresis on the first treatment day and the most rapid fall in blood pressure. The ultimate antihypertensive effect of all three drugs was similar. Tienilic acid caused a noticeable reduction in serum urate concentrations and a rise in urate clearance, in contrast to the other two agents, which caused slight urate retention. Tienilic acid and bendrofluazide caused falls and spironolactone a rise in plasma potassium concentrations. No untoward effects were seen from any of the drugs. It is concluded that tienilic acid is a moderately potent diuretic that lowers plasma urate concentrations. It may be the drug of first choice for hypertensive patients who already have gout or are likely to develop it when taking thiazide diuretics.     

Antihypertensive therapy in the prevention of stroke: what, when and for whom?

It is clear that antihypertensive regimens based on a low dose thiazide diuretic are effective for the primary prevention of stroke, particularly in older patients. In patients with diabetes mellitus who are at a higher risk of stroke, low dose thiazide diuretics and ACE inhibitors are of benefit. In those with isolated systolic hypertension, long-acting dihydropyridine calcium antagonists, in addition tolow dose thiazide diuretics, have also been shown to significantly reduce stroke risk. However, to attain sufficient lowering of blood pressure (BP) to most effectively reduce the risk of stroke (i.e. to levels of 140-150/80-85 mm Hg or lower and perhaps to <140/<80 mm Hg in patients with diabetes mellitus) combination therapy will be required. Immediately following stroke BP tends to fall spontaneously and therapy is probably not required in the great majority of patients during the first few days poststroke. If treatment is required shortly after this period, agents with a slow and gentle onset of action appear to be preferable; some preliminary data suggest that ACE inhibitors, despite lowering systemic BP, have no significant effect on cerebral blood flow. However, there is little clinical outcome data to clearly define the role of antihypertensive treatment in the early poststroke period. Whether existing antihypertensive therapy should be continued following stroke is also unclear, but such decisions may be influenced by factors such as the actual BP level, other indications for treatment (e.g. angina pectoris or cardiac failure) or the presence of dysphagia. There is more evidence to suggest that, some weeks to months following stroke (particularly a minor stroke), lower rather than higher BP is favourable, and better control of high BP with therapy reduces stroke recurrence.     

Antihypertensive efficacy and tolerability of aliskiren/hydrochlorothiazide (HCT) single-pill combinations in patients who are non-responsive to HCT 25 mg alone*

ABSTRACT

Objective: Thiazide diuretics such as hydrochlorothiazide (HCT) are a widely used first-line treatment for hypertension, but most patients will not achieve blood pressure (BP) control with HCT alone and so will require combination therapy. In this study the efficacy, safety and tolerability of a single-pill combination (SPC) of the direct renin inhibitor aliskiren with HCT were investigated in patients non-responsive to HCT 25?mg therapy.

Methods: In this study, 722 patients with hypertension and an inadequate response to 4?weeks of HCT 25?mg (mean sitting diastolic BP ≥90 and <110?mmHg) were randomized to once-daily, double-blind treatment for 8?weeks with an SPC of aliskiren/HCT 300/25?mg or 150/25?mg, or continued HCT 25?mg monotherapy. Least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from double-blind baseline were analyzed for the ITT population at week?8 endpoint.

Results: Aliskiren/HCT 300/25?mg and 150/25?mg SPCs lowered msSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5?mmHg, respectively, both significantly greater reductions than HCT 25?mg alone (7.1/4.8?mmHg; both p?<?0.001). Rates of BP control (<140/90?mmHg) were also significantly higher with aliskiren/HCT 300/25?mg (58%) and 150/25?mg (49%) than with HCT (26%; both p?<?0.001). Aliskiren/HCT 300/25?mg provided significantly greater msSBP/DBP reductions and rates of BP control than the 150/25?mg SPC dose (all p?<?0.05). Aliskiren/HCT SPC treatment showed similar tolerability to HCT alone and a numerically lower incidence of hypokalemia (serum potassium <3.5?mmol/L; aliskiren/HCT, 1.3–2.2%: HCT alone, 3.4%).

Conclusion: Aliskiren/HCT SPCs provide clinically significant BP reductions and improved BP control rates in patients who are non-responsive to HCT 25?mg monotherapy. Limitations of the study were the mainly Caucasian patient population and the non-responder design.