OBJECTIVE: The aim of this meta-analysis was to compare the 24-h antihypertensive efficacy of different treatments using the smoothness index. METHODS: Data were taken from the telmisartan ambulatory blood pressure monitoring (ABPM) clinical programme. Eleven clinical trials that randomized mild-to-moderate hypertensive patients to treatment with telmisartan 40/80 mg, losartan 50 mg, valsartan 80/160 mg, ramipril 10 mg, amlodipine 5 mg monotherapy, or with an angiotensin receptor blocker (ARB) and hydrochlorothiazide (HCTZ) 12.5/25 mg, were included. Treatment duration ranged from 4 to 14 weeks. The smoothness index was calculated according to the published formula. RESULTS: Altogether, 5188 patients were included (65% men; 52% were using telmisartan as monotherapy or in combination with HCTZ). Telmisartan 80 mg had a higher smoothness index than losartan, valsartan or ramipril (P < 0.05), and was comparable with amlodipine. All combination therapies had a higher smoothness index than monotherapy; the largest value was observed with telmisartan 80 mg and HCTZ 12.5 mg. Overall, the smoothness index was lower in men, older patients, black patients, smokers and in those with lower baseline blood pressure (P < 0.05). CONCLUSION: The smoothness index was affected by age, race, sex, behavioural and haemodynamic factors. It was also able to differentiate the 24-h blood pressure effects of antihypertensive drugs, with telmisartan and amlodipine achieving the highest values, possibly because of their long plasma half-lives. All combination therapies had a higher smoothness index than monotherapy. An understanding of the relative effects of different antihypertensives on the smoothness index may help to differentiate their effectiveness in reducing blood pressure-related cardiovascular risk.

AbstractObjective- Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of Type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of the present study was to generate novel hypothalamic markers of hypoglycemia and to use these to assess mechanisms mediating HAAF and its reversal. Research design and methods- Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia. Results- A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone, but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, were acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, CPT-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone, but not valsartan. Conclusions- Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward beta oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.

This study aimed to improve the pH-independent solubility and dissolution characteristics of valsartan via the preparation of solid dispersions (SD) with poloxamer 407. SDs was prepared by using the solvent method at various drug-polymer ratios and their dissolution characteristics were examined at different pHs. Oral pharmacokinetics of SDs was also evaluated in rats. Compared to the untreated powder, SDs significantly improved the dissolution rate as well as the extent of drug release at low pH. Particularly, SD having the drug-polymer ratio of 1:5 exhibited pH-independent dissolution of valsartan, resulting in the rapid and complete drug release over the pH range of 1.2 to 6.8. The improved dissolution of valsartan via SD formulation appeared to be well correlated with the enhanced oral exposure of valsartan in rats. SDs increased C(max) and AUC(0-24) of valsartan by 2-7 folds in rats, implying that SDs should be effective to improve the bioavailability of valsartan. In conclusion, SDs containing poloxamer 407 appeared to be effective to improve the pH-independent dissolution and oral absorption of valsartan.

During wastewater treatment, many organic micropollutants undergo microbially mediated reactions resulting in the formation of transformation products (TPs). Little is known on the reaction pathways that govern these transformations or on the occurrence of microbial TPs in surface waters. Large sets of biotransformation data for organic micropollutants would be useful for assessing the exposure potential of these TPs and for enabling the development of structure-based biotransformation prediction tools. The objective of this work was to develop an efficient procedure to allow for high-throughput elucidation of TP structures for a broad and diverse set of xenobiotics undergoing microbially mediated transformation reactions. Six pharmaceuticals and six pesticides were spiked individually into batch reactors seeded with activated sludge. Samples from the reactors were separated with HPLC and analyzed by linear ion trap-orbitrap mass spectrometry. Candidate TPs were preliminarily identified with an innovative post-acquisition data processing method based on target and non-target screenings of the full-scan MS data. Structures were proposed following interpretation of MS spectra and MS/MS fragments. Previously unreported microbial TPs were identified for the pharmaceuticals bezafibrate, diazepam, levetiracetam, oseltamivir, and valsartan. A variety of previously reported and unreported TPs were identified for the pesticides. The results showed that the complementary use of the target and non-target screening methods allowed for a more comprehensive interpretation of the TPs generated than either would have provided individually.

BACKGROUND: The safety of once-daily (qd) dosing of valsartan in heart failure (HF) patients is not known. HYPOTHESIS: This 10-week, double-blind trial examined the relative safety and efficacy of valsartan administered qd versus twice-daily (bid). METHODS: HF patients (NYHA class II-III) receiving diuretics (87%), angiotensin-converting enzyme inhibitors (98%), beta-blockers (92%), aldosterone antagonists (25%), or digoxin (32%) were randomized to valsartan 40 mg bid (n = 60) or 80 mg qd (n = 55) and titrated to a maximum dose of 320 mg/day; doubling the dose every 2 weeks. Clinical and biochemical parameters were measured at Weeks 2, 4, 6, and 10. RESULTS: The average dose of valsartan at the end of study was 245 mg in the bid group vs 256 mg in the qd group (P = NS). Similar proportions of patients tolerated qd vs bid dosing (bid 67% vs qd 68%). Outcome measures including reduction in blood pressure, incidence of hypotension, renal impairment, orthostatic dizziness or fatigue, changes in serum K(+), creatinine, cystatin-C, and estimated glomerular filtration rate were similar between the 2 groups at all time-points. Brain natriuretic peptide levels decreased and plasma renin activity increased from baseline by the same amount in both groups at all time-points. CONCLUSION: Valsartan administered qd has a similar safety and tolerability profile with comparable 24-hour RAAS blockade, as assessed by increases in PRA, as bid dosing in patients with moderate to severe (NYHA class II-III) heart failure.

To the Editor: In their article on the valsartan portion of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial (April 22 issue),(1) McMurray et al. report a significant reduction of 14% in the relative hazard of diabetes among patients receiving valsartan, as compared with placebo. However, the investigators did not address the presence of two possibly confounding factors. First, there was a higher prevalence of the metabolic syndrome among patients assigned to placebo than among those assigned to valsartan, which could have predisposed those patients to diabetes.(2) It is unclear whether this difference was taken into . . .

Inhalation exposure to fine concentrated ambient particles (CAPs) increases cardiac oxidants by mechanisms involving modulation of the sympathovagal tone on the heart. Angiotensin-II is a potent vasoconstrictor and a sympatho-excitatory peptide involved in the regulation of blood pressure. We hypothesized that increases in angiotensin-II after fine particulate matter (PM) exposure could be involved in the development of cardiac oxidative stress. Adult rats were treated with an angiotensin-converting enzyme (ACE) inhibitor (benazepril((R))), or an angiotensin receptor blocker (ARB; valsartan((R))) before exposure to fine PM aerosols or filtered air. Exposures were carried out for 5 hours in the chamber of the Harvard fine particle concentrator (fine PM mass concentration: 440 +/- 80 mug/m(3)). At the end of the exposure the animals were tested for in situ chemiluminescence (CL) of the heart, thiobarbituric acid reactive substances (TBARS) and for plasma levels of angiotensin-II. Also, continuous electrocardiogram (ECG) measurements were collected on a subgroup of exposed animals. PM exposure was associated with statistically significant increases in plasma angiotensin concentrations. Pre-treatment with the ACE inhibitor effectively lowered angiotensin concentration, whereas ARB treatment led to increases in angiotensin above the PM-only level. PM exposure also led to significant increases in heart oxidative stress (CL, TBARS), and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events.

Background: A majority of hypertensive patients require >/= 2 agents to achieve target blood pressure (BP). Methods: This 52-week, multicentre, open-label, randomised extension trial to a previously reported double-blind, placebo-controlled study evaluated the safety and efficacy of amlodipine/valsartan (Aml/Val) combination. Patients who successfully completed the core study without serious drug-related adverse events (AEs) and mean sitting systolic BP (MSSBP)/mean sitting diastolic BP (MSDBP) </= 150/95 mmHg were eligible to enter the extension and be treated with Aml/Val 2.5/80 or 5/80 mg. After 4 weeks of treatment, patients underwent force-titration to receive 5/160 mg (low dose) or 10/160 mg (high dose) for 48 weeks. Addition of hydrochlorothiazide (HCTZ) 12.5 mg was permitted if BP was >/= 140/90 mmHg at Week 8 or later. Patients could be down-titrated to the prior lower combination dose with or without HCTZ if an intolerable AE occurred. Safety evaluations included monitoring of AEs. Efficacy variables were change from baseline in MSDBP (primary) and MSSBP (secondary). Results: Of 1246 patients randomised, 1075 (86.3%) completed the extension study. At week 52 end-point, change in MSSBP/MSDBP from core study baseline was -22.1/-17.2 mmHg for low-dose regimen and -22.8/-18.1 mmHg for high-dose regimen. For both regimens, reductions in BP were sustained over 52 weeks and mean BP maintained below approximately 135/85 mmHg at all visits. Frequent AEs in the low- and high-dose regimens were peripheral oedema (9.7% and 17.1% respectively), nasopharyngitis (8.1% and 7.2%), and dizziness (5.2% and 7.0%). Incidence of serious AEs was 3.7% with low dose and 4.1% with high dose. Conclusion: The combination of Aml/Val with the optional addition of HCTZ produced clinically significant and persistent reductions in BP over 52 weeks with a favourable tolerability profile.

The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0+/-1.8 g g(-1) to 0.8+/-0.8 g g(-1) (P=0.0242) in Olm-G and from 1.4+/-1.3 g g(-1) to 0.9+/-1.0 g g(-1) (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients.Hypertension Research advance online publication, 12 August 2010; doi:10.1038/hr.2010.145.

Objective Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinised. The VALsartan In Acute myocardial iNfarcTion, a large multinational, pragmatic, randomised, double-blind, multicentre trial, was retrospectively evaluated for evidence of research conduct consistent with a performance "learning curve". Design Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (eg, first, second), recruitment rate and first enrolment relative to study start date. Setting Computerised data from a trial coordinated by an academic research organisation collaborating with 10 academic and 2 commercial research organisations and an industry sponsor. Interventions 931 sites enrolled 14 703 patients. Departures were restricted to the first year. Exclusions included patient's death or loss to follow-up within 12 months and subjects enrolled 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment and later start date. Methods and results 12 367 patients at 931 sites were analysed. Departures were more common for patients enrolled earlier at a site (p<0.0001). For example, compared with the 30th patient, the first had 47% more departures. Departures were also more common with slower enrolment and site start closer to the trial start date (p<0.0001). Similar patterns existed for queries. Conclusions Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a "learning curve". Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct.

INTRODUCTION: Hypertension is an important risk factor for cardiovascular disease and its management requires improvement. New treatment strategies are needed. AIMS: This review analyses one of these strategies, which is the development of effective and safe combination therapy. Indeed, at least two antihypertensive agents are often needed to achieve blood pressure control. Exforge((R)) (Novartis) is a new drug combination of the calcium channel blocker, amlodipine, and the angiotensin II receptor blocker, valsartan. EVIDENCE REVIEW: The amlodipine/valsartan combination is an association of two well-known antihypertensive products with specific targets in cardiovascular protection, namely calcium channel blockade and antagonism of the renin-angiotensin-aldosterone system. This kind of association, with neutral metabolic properties and significant antihypertensive efficacy, could be a useful new antihypertensive product. Currently available data have shown that this new combination is well-tolerated and effective even in severe hypertension. CLINICAL VALUE: Clinical trials are ongoing for further assessment of the efficacy, compliance, and safety of this combination and its congeners. No data exist to prove that the amlodipine/valsartan combination is better than other antihypertensive strategies for cardiovascular or renal protection, but some trials with other combination therapies show such potential advantage.

OBJECTIVE: Vulnerability profiling, an alternative to deterministic risk assessment, offers clinicians a more intuitive but empirically-grounded assessment of patient risk. This study aimed to determine whether a heuristic profile of high vulnerability is an independent predictor of uncontrolled hypertension. METHODS: Secondary analysis of prospective observational study data on 2999 hypertensive patients treated with valsartan. Predictive validity of vulnerability profiling for first-line, second-line, and first-or-second-line antihypertensive treatment was inferred from 1) logistic regression models with adequate statistical fit, 2) statistically significant odds ratios for uncontrolled BP for the high-vulnerability cluster exceeding 1.00, and 3) correct classification rates for patients' BP control status. RESULTS: All models of uncontrolled BP were significant (P < 0.001); all odds ratios for the high-vulnerability cluster were greater than 1.00 and significant (P < 0.001). Correct classification rates for the highly-vulnerability cluster on uncontrolled BP after first-line, second-line, or either treatment were 91.1%, 61.2%, and 93.5% for systolic BP; 74.5%, 65.8%, and 76.7% for diastolic BP; and 92.8%, 65.3%, and 94.6% for combined systolic and diastolic BP. CONCLUSION: The heuristic profile of "later, lazier, and unluckier" is an intuitive and valid tool to help identify patients at greater risk for poor BP control seen in general practice.

Early combination therapy is increasingly recommended in hypertension management because of increased risk of adverse effects with high-dose monotherapy. However, this risk is not necessarily increased for high doses of angiotensin receptor blockers (ARB). ValTop study compared efficacy and safety of high vs. conventional dose of valsartan in hypertensive patients. ValTop was a controlled, randomized, double-blind trial. Of 6035 screened subjects, 4004 mild-to-moderate hypertensive patients (mean seated diastolic blood pressure (MSDBP) 90-109 mm Hg) started 4-week open-label treatment with valsartan 160 mg. Of them, 3776 were randomized to receive valsartan 160 mg (N=1900) or 320 mg (N=1876) o.d. for 4 weeks. In 28-week open-label extension study, all participating patients (N=642) received valsartan 320 mg. Valsartan 160 mg reduced MSDBP by 10.0 mm Hg in the initial open-label phase. Further BP reductions in the double-blind phase were significantly (P<0.0001) greater in the 320 mg group than in the 160 mg group for MSDBP (1.6+/-0.18 mm Hg vs. 0.5+/-0.18 mm Hg) and mean seated systolic BP (3.3+/-0.31 mm Hg vs. 0.7+/-0.31 mm Hg). The size of the additional effect of the 320 mg dose on BP was similar in subjects controlled or not by the initial 160 mg dose. Adverse event (AE) rates were similar in both treatment groups, drug-related AEs occurring in <5% of subjects in each phase. High-dose valsartan is safe and effective in uncomplicated mild-to-moderate hypertension independently of the initial response to a moderate dose. High-dose ARB monotherapy may thus be a viable option in hypertension management.Hypertension Research advance online publication, 5 August 2010; doi:10.1038/hr.2010.120.

The protective effect of combination therapy with valsartan and aliskiren against renal fibrosis remains to be defined. This study was undertaken to examine the protective effects of the combination of valsartan and aliskiren against renal fibrosis induced by unilateral ureteral obstruction (UUO). Combination therapy with Valsartan (15 mg/kg/day) and aliskiren (10 mg/kg/day), valsartan monotherapy (30 mg/kg/day), and aliskiren monotherapy (20 mg/kg/day) all significantly ameliorated the increase of BUN and the degree of hydronephrosis determined by the increase of weight and length of the obstructed kidney. The dose titration study and blood pressure measurement confirmed that the combination therapy provided a greater benefit independent from the vasodilatory effect. There were no significant changes of serum levels of creatinine, sodium, and potassium in UUO rats and any treatment groups. Combination therapy also attenuated UUO related increases on the scores of tubular dilatation, interstitial volume, interstitial collagen deposition, alpha-smooth muscle actin, the activation of ERK 1/2, the infiltration of monocytes/macrophages, the mRNA expression of snail-1, and transforming growth factor-beta1 to a greater extent compared with aliskiren or valsartan used alone. The mRNA expression of renin and (pro)renin receptor significantly increased after UUO. Combination therapy and monotherapy of valsartan and aliskiren had a comparable enhancing effect on the mRNA expression of renin, whereas all these treatments did not affect the expression of the (pro)renin receptor. In conclusion, a DRI in conjunction with an ARB exerts increased renal protection against renal fibrosis and inflammation during obstruction over either agent alone.

Background Dual renin-angiotensin system (RAS) blockade, mostly by combining an angiotensin converting enzyme (ACE) inhibitor with an angiotensin receptor blocker (ARB), is increasingly used in patients with hypertension and diabetes and/or proteinuria and in those with resistant heart failure. However, in the zest of achieving greater nephroprotection and cardioprotection, even patients with uncomplicated essential hypertension are not uncommonly treated with dual RAS blockade. Evidence In 2003 the COOPERATE trial, seemed to confirm that dual RAS blockade was beneficial and that proteinuria reduction was synonymous with nephroprotection. This study had to be withdrawn recently attesting to the suspicion that the data looked to good to be true. Moreover, the large prospective ONTARGET data argue against a nephroprotective effect of dual RAS blockade and together with renal findings from ACCOMPLISH, cast doubt on albuminuria/proteinuria being a reliable surrogate endpoint for renal outcome. Although in heart failure, dual RAS blockade had some benefit without reducing mortality, there remains a distinct safety issue with regard to hyperkalemia and elevated creatinine. Neither in ischaemic heart disease nor in left ventricular hypertrophy had dual RAS blockade any benefits when compared with single RAS blockade. Of note, the combination of an ACE inhibitor with an ARB was recently shown to reduce the risk of dementia. All dual RAS blockade may be created equal and the combination of valsartan with aliskiren, a direct renin inhibitor will be evaluated in diabetic patients in the prospective, randomized ALTITUDE study. Conclusions For the time being, given the adverse effects and lack of consistent survival benefits, the use of dual RAS blockade should be avoided unless ironclad data emerge to the contrary.

OBJECTIVE: To investigate the molecular mechanism of tanshinone II A (TSN) for preventing left ventricular hypertrophy (LVH) by studying the expressions of angiotensin I type 1 receptor (AT1R), transforming growth factor beta1 (TGF-beta1) and intracellular signal protein gene (Smads gene) in the hypertrophic myocardium of hypertensive rat models induced by pressure over-loading. METHODS: SD rat model of LVH was established by abdominal aorta constriction. The model animals were randomly divided into 4 groups 4 weeks after modeling, the untreated model control group (C1), the two tested groups (T1 and T2) treated respectively with high (20 mg/kg) and low (10 mg/kg) dose of TSN II A per day via intraperitoneal injection, and the positive control group (C2) treated with 10 mg/kg of Valsartan per day by gastric perfusion, with 8 animals in each group. Besides, 8 SD rats managed with sham operation were set up as the sham-operated control group (C3) After an 8-week treatment, the caudal arterial pressure, left ventricular mass index (LVMI), myocardial fiber dimension (MFD, by pathologic examination with HE staining) in rats were measured. Meanwhile, mRNA expression of AT1R, protein expression of TGF-beta1 and activity of Smad-3, 4, 7 in the ventricular tissue were detected by RT-PCR analysis and Western blotting respectively. RESULTS: (1) Blood pressure in Group T1 and T2 was unchanged after treatment, which was significantly higher than that in Group C2 and C3 (P < 0.01, P < 0.05). (2) LVMI and MFD in Group T1, T2 and C2 were higher than that in Group C3 (P < 0.01), but remarkably lower than that in Group C1 (P < 0.01). (3) Levels of AT1R, TGF-beta1 and Smad-3 expression increased significantly in the model rats (P < 0.01), but they were down-regulated in Group T1 and C2, and the TGF-beta1 regulating effect in the C2 was more potent than that in Group T1 and T2 (P < 0.05). (4) Protein expression of Smad-7 was up-regulated in Goup T1, T2 and C2 obviously (P < 0.01), and the effect in Group T1 was superior to that in C2 (P < 0.05). CONCLUSION: The myocardial hypertrophy inhibition effect of TSN II A is a blood pressure independent process, and it may be related to the inhibition of AT1R mRNA expression and blocking of TGF beta1/Smads signal pathway.

Abstract Objective: To compare blood pressure (BP) goal achievement associated with the use of valsartan-based single pill combinations (SPCs) vs. angiotensin II receptor blocker (ARB)-based free combinations (FCs) among adult hypertension patients. Research design and methods: Data were collected from physician-administered chart review of adult hypertension patients in the South Central region. All patients had uncontrolled BP before initiating one of the index therapies (SPCs: valsartan/amlodipine or valsartan/hydrochlorothiazide [HCTZ], FCs: ARB + calcium channel blocker [CCB] or ARB + HCTZ) between 07/2008 and 06/2009. Up to three BP measures were collected starting from 45 days after the therapy initiation. BP goal was <130/80 mmHg for patients with diabetes, chronic renal disease or coronary heart disease; or <140/90 mmHg for patients without these comorbidities. The Kaplan-Meier method with log-rank test was used to compare rates of BP goal achievement associated with valsartan-based SPCs vs. ARB-based FCs over time. Cox proportional hazard models were used to estimate the likelihood of BP goal achievement associated with SPCs vs. FCs, controlling for demographics, baseline BP, hypertension history, comorbidities, prior and concurrent use of anti-hypertensive medications, and physician specialty. Results: The study included 812 patients: 414 on valsartan-based SPCs (209 on valsartan/amlodipine and 205 on valsartan/HCTZ) and 398 on ARB-based FCs (200 on ARB + CCB and 198 on ARB + HCTZ). The ARBs in the FC group included valsartan, losartan, olmesartan, telmisartan, irbesartan and candesartan. In the ARB FC group, the most commonly used ARB and CCB were valsartan (29.1%) and amlodipine (81.5%), respectively. During the observation period (81 days for valsartan SPC patients and 90 days for ARB FC patients), 65.9% of valsartan SPC patients and 55.8% of the ARB FC patients achieved BP goal. Over time, the rates of BP goal achievement were consistently higher among valsartan SPC vs. ARB FC patients (p = 0.01): 31.1% vs. 28.9% and 69.1% vs. 59.2% at month 3 and 6 after therapy initiation, respectively. Cox regression confirmed that valsartan SPC patients were more likely to achieve BP goal (HR = 1.22; p = 0.05). A similar trend was observed in the subgroup analyses comparing SPC of valsartan/amlodipine vs. FCs of ARB + CCB and SPC of valsartan/HCTZ vs. FCs of ARB + HCTZ. Limitations: Non-randomization of treatments, limited generalizability, and no records of BP measures within 45 days. Conclusions: Patients using valsartan-based SPCs were significantly more likely to achieve BP goal than those treated with ARB-based FCs in the real-world clinical practice in the South Central region. The significance was achieved at two-sided alpha = 0.05.

PURPOSE: Single-pill-combination (SPC) antihypertensive drug products have been shown to improve compliance but are associated with higher acquisition costs. This study compared the clinical and economic outcomes associated with the use of an SPC of amlodipine/valsartan (trade name Exforge) with the outcomes from conventional combination therapy in patients failing to respond to initial monotherapy with either a dihydropyridine calcium channel blocker (DHP-CCB) or an angiotensin receptor blocker (ARB). DESIGN: We conducted a retrospective cohort study of hypertensive patients failing to respond to monotherapy with either a DHP-CCB or an ARB who were switched to an SPC of amlodipine/valsartan (SPC group) or to treatment that could not include any SPC (control group). The groups were matched for age, gender, race, baseline blood pressure (BP), and comorbidities. The primary outcomes of the study included the proportion of patients achieving BP targets, the absolute change in BP from baseline, the proportion of patients discontinuing drug therapy because of side effects, the proportion of patients non-compliant with drug therapy, and health care resource utilization and costs. PRINCIPAL FINDINGS: Fifty-eight SPC patients achieved BP targets compared with 47 control patients (P = 0.119). The absolute reduction in BP was significantly greater in the SPC group (-22.8 +/- 6.9/-19.3 +/- 5.2 mmHg) than in the control group (-20.6 +/- 6.4/-17.8 +/- 5.6 mmHg) (P < 0.03). Significantly fewer patients discontinued anti-hypertensive therapy because of side effects and noncompliance in the SPC group compared with the control group (both P = 0.042). SPC patients accrued fewer clinic visits, laboratory tests, and electrocardiograms but had higher drug acquisition costs. Median medical therapy costs were significantly lower in the SPC group at the end of the 6-month follow-up, primarily because of lower costs for clinic visits. CONCLUSION: The use of the SPC of amlodipine/valsartan was associated with greater absolute BP reductions and fewer antihypertensive drug discontinuations because of side effects and noncompliance compared with the use of the individual drugs. Although the acquisition cost of the SPC was greater than that of the individual drugs, SPC combination therapy resulted in fewer clinic visits, laboratory tests, and electrocardiograms. As a result, the total cost of SPC therapy was significantly less than that associated with the use of the individual drug components.

BACKGROUND AND OBJECTIVES: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. RESULTS: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. CONCLUSIONS: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.