High-dose Angiotensin Receptor Blocker Research Articles

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.

Efficacy and Safety of Angiotensin-Converting Enzyme Inhibitor in Combination with Angiotensin-Receptor Blocker in Chronic Kidney Disease Based on Dose: A Systematic Review and Meta-Analysis.

Background: The purpose of this meta-analysis was to evaluate the controversy of angiotensin-converting enzyme inhibitor (ACEI) in combination with angiotensin-receptor blocker (ARB) in the treatment of chronic kidney disease (CKD) based on dose. Methods: PubMed, EMBASE, and Cochrane Library were searched to identify randomized controlled trials (RCTs) from inception to March 2020. The random effects model was used to calculate the effect sizes. Potential sources of heterogeneity were detected using sensitivity analysis and meta-regression. Results: This meta-analysis of 53 RCTs with 6,375 patients demonstrated that in patients with CKD, ACEI in combination with ARB was superior to low-dose ACEI or ARB in reducing urine albumin excretion (SMD, −0.43; 95% CI, −0.67 to −0.19; p = 0.001), urine protein excretion (SMD, −0.22; 95% CI, −0.33 to −0.11; p < 0.001), and blood pressure (BP), including systolic BP (WMD, −2.89; 95% CI, −3.88 to −1.89; p < 0.001) and diastolic BP (WMD, −3.02; 95% CI, −4.46 to −1.58; p < 0.001). However, it was associated with decreased glomerular filtration rate (GFR) (SMD, −0.13; 95% CI, −0.24 to −0.02; p = 0.02) and increased rates of hyperkalemia (RR, 2.07; 95% CI, 1.55 to 2.76; p < 0.001) and hypotension (RR, 2.19; 95% CI, 1.35 to 3.54; p = 0.001). ACEI in combination with ARB was more effective than high-dose ACEI or ARB in reducing urine albumin excretion (SMD, −0.84; 95% CI, −1.26 to −0.43; p < 0.001) and urine protein excretion (SMD, −0.24; 95% CI, −0.39 to −0.09; p = 0.002), without decrease in GFR (SMD, 0.02; 95% CI, −0.12 to 0.15; p = 0.78) and increase in rate of hyperkalemia (RR, 0.94; 95% CI, 0.65 to 1.37; p = 0.76). Nonetheless, the combination did not decrease the BP and increased the rate of hypotension (RR, 3.95; 95% CI, 1.13 to 13.84; p = 0.03) compared with high-dose ACEI or ARB. Conclusion: ACEI in combination with ARB is superior in reducing urine albumin excretion and urine protein excretion. The combination is more effective than high-dose ACEI or ARB without decreasing GFR and increasing the incidence of hyperkalemia. Despite the risk of hypotension, ACEI in combination with ARB is a better choice for CKD patients who need to increase the dose of ACEI or ARB (PROSPERO CRD42020179398).

Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis

We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.

Angiotensin receptor blockers (ARB) outperform angiotensin-converting enzyme (ACE) inhibitors on ischemic stroke prevention in patients with hypertension and diabetes — A real-world population study in Taiwan

BackgroundCombination therapy with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) has been stressed for its comprehensive blocking of the renin-angiotensin-aldosterone system, but the evidence for their respective safety and efficacy, in particular with stroke prevention, is still insufficient in population-based follow-up studies in the real world. MethodsUsing Taiwan's National Health Insurance claims data, we identified 5445 subjects aged 18years and older who had newly diagnosed hypertension in 1997–2010, from them diagnosed type 2 diabetes later. Among them, 2161 patients took ACEI, 1703 patients took ARB, 165 patients took both ACEI and ARB, and 1416 patients had neither. ResultsDuring the follow-up period, the stroke incidence density was the lowest (23.02 per 1000person-years) in ARB group, followed by the group with neither medication, the ACEI group, and ARB/ACEI combination group (24.06, 30.23, and 37.86 per 1000person-years, respectively). Compared with patients taking neither medication, the adjusted hazard ratios (HRs) were 1.27 (95% CI 1.02–1.58) for ACEI group, 0.95 (95% CI 0.74–1.22) for ARB group, and 1.56 (95% CI 0.99–2.47) for ARB/ACEI combined group. Greater reduction in risk of stroke was observed in patients with high dose ARB (adjusted HR=0·42, 95% CI 0·24–0·75). ConclusionOur findings support the practice that ARBs could be used, from the perspective of stroke prevention, as a first-line antihypertensive drug for patients with both hypertension and diabetes. The group with ARB regimen reduces 26% of stroke in contrast to the group with ACEI regimen.

Fibrosis and renal aging

Glomerulosclerosis and interstitial fibrosis increase in the aging kidney, and glomerular filtration rate (GFR) decreases with increasing age. Decreases in stem cell number and function contribute to renal aging. High-dose angiotensin receptor blocker (ARB) not only slows the progression of glomerular and vascular sclerosis in aging but can also induce regression of these processes independently of its hemodynamic actions. By using new interventions, such as peroxisome proliferator activator receptor gamma (PPARγ) agonist, we can manipulate the process of renal aging by regulating stem cells and other mechanisms.

Therapeutic impact of the single fixed-dose combination with a high-dose angiotensin-receptor blocker and a low-dose thiazide diuretic in the management of hypertension: awaiting further accumulation of clinical evidence.

Therapeutic impact of the single fixed-dose combination with a high-dose angiotensin-receptor blocker and a low-dose thiazide diuretic in the management of hypertension: awaiting further accumulation of clinical evidence

Genomics and Disease Progression in IgA Nephritis

Apart from clinical, histological and biochemical indices, genomics are now being employed to unravel the pathogenetic mechanisms in the disease progression of IgA nephritis (IgAN). The results of angiotensin converting enzyme (ACE) gene polymorphism have been controversial. Those patients with the DD genotype seem to have a poorer prognosis. However, with high dose angiotensin receptor blocker (ARB) therapy, the ACE gene polymorphism status of a patient may no longer be a matter for concern as those with the DD genotype would also respond favourably to high dose ARB therapy. Association studies with gene sequencing and haplotypes have suggested that multiple genes are involved in the pathogenesis of IgAN. Some workers have reported a synergistic effect in the combined analysis of AGT-M235T and ACE I/D polymorphism. With the use of deoxyribo nucleic acid (DNA) microarray, tens of thousands of gene expressions genome-wide can be examined together simultaneously. A locus of familial IgAN has been described with strong evidence of linkage to IgAN1 on chromosome 6q22-23. Two other loci were reported at 4q26-31 and 17q12-22. DNA microarray techniques could also help in the identification of specific pathogenic genes that are up- or down-regulated and this may allow genome wide analyses of these genes and their role in the pathogenesis and progression of IgAN. Recently, using genome-wide association studies (GWAS) more loci for disease susceptibility for IgAN have been identified at 17p13, 8p23, 22q12, 1q32 and 6p21.

A retrospective Aliskiren and Losartan study in non-diabetic chronic kidney disease.

To assess the efficacy of combined Aliskiren and Losartan vs high dose Losartan and Aliskiren alone in chronic kidney disease (CKD). This is a retrospective study of 143 patients with non-diabetic CKD comparing combined Aliskiren (150 mg/d) with Losartan (100 mg/d) therapy vs High dose Angiotensin receptor blockers (ARB) (Losartan 200 mg/d) and the third group Aliskiren (150 mg/d) alone. This study involved only patient medical records. Entry criteria included those patients who had been treated with the above drugs for at least 36 mo within the 5 years period; other criteria included proteinuria of 1 g or more and or CKD Stage 3 at the start of the 36 mo period. The study utilised primary renal end points of estimated Glomerular Filtration Rate (eGFR) < 15 mL/min or end stage renal failure. Patients treated with high dose ARB compared to the other two treatment groups had significantly less proteinuria at the end of 36 mo (P < 0.007). All 3 groups had significant reduction of proteinuria (P < 0.043, P < 0.001). Total urinary protein was significantly different between the 3 groups over the 3-year study period (P = 0.008), but not eGFR. The changes in eGFR from baseline to each year were not significantly different between the 3 therapeutic groups (P < 0.119). There were no significant differences in the systolic and diastolic blood pressure between the 3 drug groups throughout the 3 years. The incidence of hyperkalemia (> 5.5 mmol/L) was 14.2% (7/49) in the Combined Aliskiren and ARB group, 8.7% (4/46) in the Aliskiren alone group and 6.3% (3/48) in the High dose ARB group (P < 0.001). This study in non-diabetic CKD patients showed that Combination therapy with Aliskiren and ARB was effective but was not safe as it was associated with a high prevalence of hyperkalaemia.

Feasibility of Regression of Hypertension Using Contemporary Antihypertensive Agents

Recently, we reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release (CR) resulted in a sustained regression of hypertension in humans. Patients aged 30 to 59 years with untreated stage 1 essential hypertension and a family history of hypertension were treated with the antihypertensive agents candesartan (n = 124) or nifedipine CR (n = 120). After 1 year of treatment (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. In phase 1, after 1 year of treatment a similarly substantial BP decrease was seen in the candesartan (-24.5/16.1 mm Hg) and nifedipine (-26.8/18.0 mm Hg) groups. In phase 2 there was a substantial reoccurrence of hypertension; at the study end, only 1 patient was able to continue without antihypertensive medication. However, a Kaplan-Meier analysis revealed a significant delay of reoccurrence of hyper tension (P = 0.0001) in the candesartan group. One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard doses used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

Losartan/hydrochlorothiazide combination therapy surpasses high-dose angiotensin receptor blocker in the reduction of morning home blood pressure in patients with morning hypertension.

Angiotensin receptor blockers (ARBs) are the first-line antihypertensive agents. In clinical practice, it is often difficult to achieve the recommended blood pressure level by ARBs in their ordinal dosages alone. This study examined the practical efficacy of a combination therapy of ARB with thiazide diuretics for lowering morning home blood pressure (MHBP) in comparison to high-dose ARB therapy in patients with morning hypertension administered an ordinal dosage of ARB. This study was performed in a prospective, randomized, open-labeled and blind-endpoint fashion. Patients were considered to have morning hypertension when their self-measured systolic MHBPs were 135mmHg or higher, irrespective of their diastolic MHBP and office blood pressures (OBPs). Forty-eight outpatients with morning hypertension receiving the ordinal dosage of ARB were given either losartan/hydrochlorothiazide (n = 26) or high-dose ARB (n = 22) in place of their previously prescribed ARB. No change in any medication was permitted during this period. Decreases of both systolic and diastolic MHBP after 3 months of treatment were significantly greater in the losartan/hydrochlorothiazide group than in the high-dose ARB group (p < 0.05, respectively). The ratio of adverse events was somewhat high (23.1% in the losartan/hydrochlorothiazide group, 9.1% in the high-dose ARB group, respectively). However, there were no significant differences in any particular adverse event between groups. This study suggested losartan/hydrochlorothiazide might be superior to high-dose ARB for reducing morning home blood pressure.

Synergy of antihypertensives in elderly patients with CKD

A recent study reports that the combination of an angiotensin-receptor blocker (ARB) and a calcium-channel blocker (versus a high-dose ARB) is associated with improved blood pressure control and reduced cardiovascular, cerebrovascular and heart failure events in an elderly chronic kidney disease population. This finding raises the possibility of using fixed-dose drug combinations to improve efficacy and compliance of antihypertensive medications.

1014 Regression of atherosclerosis in apolipoprotein-E deficient mice is feasible using high-dose angiotensin receptor blocker

Objectives: Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice. Methods and results: Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose ARB caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose ARB. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol:cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after the treatment with high-dose ARB, while biglycan and ACAT1 expressions were decreased. Conclusion: These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose ARB, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

573 Antihypertensive efficacy and safety of Losartan/hydrochlorothiazide vs. high-dose angiotensin receptor blocker (ARB) in patients with uncontrolled hypertension

Objectives: According to the current guidelines, archiving strict blood pressure control is essential to reduce cardiovascular events in patients with hypertension. The aim of this study was to evaluate antihypertensive efficacy and safety of losartan/hydrochlorothiazide (Los/HCTZ) combination drug vs. high-dose angiotensin receptor blocker (ARB) in patients with uncontrolled hypertension. Methods: This study was conducted at 11 centers for the KAHT-Trial group. A total of 65 hypertensive patients receiving regular-dose ARB therapy whose BP remained above 140/90 mmHg were prospectively enrolled. The patients were randomly assigned to receive Los/HCTZ combination drug (Los/HTCZ group, n = 67) or high-dose ARB (high-dose ARB group, n = 68) and followed for 1year. Results: After 3 months of treatment, BP significantly decreased from 157 ± 12/87 ± 9 mmHg to 137 ± 14/78 ± 8 mmHg in the Los/HCTZ group and from 158 ± 12 /91 ± 12 mmHg to 139 ± 12/80 ± 8 mmHg in the high-dose ARB group. Decreases in BP were well-maintained for 1year in the both groups. However, decreases in BP were not different between the two groups. After 1 year of treatment, levels of HbA1c, eGFR, plasma glucose, cholesterol and uric acid showed no significant changes in the both groups. Conclusions: Our results suggest that Los/HCTZ combined therapy was effective in reducing uncontrolled hypertension without deteriorating glucose, lipid and uric acid metabolism as well as high-dose ARB. Los/HCTZ combined therapy may have beneficial effect in terms of tolerability and medical economics.

Strong suppression of the renin–angiotensin system has a renal-protective effect in hypertensive patients: High-dose ARB with ACE inhibitor (Hawaii) study

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.

Effectiveness and safety of high-dose valsartan monotherapy in hypertension treatment: the ValTop study

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.

Effects of blood pressure and the renin-angiotensin system on platelet activation in type 2 diabetes.

Aims/Introduction: Platelet-derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high-dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes. The study subjects consisted of 28 type 2 diabetes patients with blood pressure ≥130/80 mmHg who were treated with valsartan (80 mg daily). The patients were randomly assigned to take either 80 mg of telmisartan (Tel group) or 160 mg of valsartan (Val group) and then were followed up for 24 weeks. Thereafter, the patients were switched to combination therapy (5 mg of amlodipine with 40 mg of telmisartan [Tel group] or 80 mg of valsartan [Val group]) for 12 weeks. Although the ambulatory blood pressure did not change, the PDMP levels were significantly decreased from baseline to week 24 (high dose ARB). In contrast, combination therapy reduced both blood pressure and PDMP levels compared with the baseline. Although the PDMP level was significantly correlated with the morning BP elevation at baseline and week 36 (combination therapy), this same relationship was not found at week 24. There were no significant differences in the blood pressure and PDMP levels between the two groups. Patients with morning hypertension might be at risk for cardiovascular diseases. High-dose renin-angiotensin system inhibition and blood pressure control are both considered to reduce cardiovascular events in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00048.x, 2010).

Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity.

Blood pressure-lowering and antiproteinuric effect of switching from high-dose angiotensin receptor blockers to normal-dose telmisartan and low-dose hydrochlorothiazide in hypertensive patients with chronic kidney disease

We evaluated the changes in the blood pressure and urinary protein excretion in poorly controlled hypertensive and proteinuric patients with mild to moderate chronic kidney disease (CKD) after switching from the high-dose angiotensin receptor blockers (ARBs) to a combination of normal-dose telmisartan (40 mg) and low-dose hydrochlorothiazide (HCTZ; 12.5 mg). 60 adults with Stages 2 - 3 CKD who had been receiving high-dose ARBs and had not achieved their target blood pressure of 130/80 mmHg were switched to a combination of telmisartan (40 mg) and HCTZ (12.5 mg) once daily for a 12-week study period. We measured the blood pressure, pulse rate, urinary protein excretion, and total monthly drug costs before and after the switch. The mean systolic blood pressure dropped from 153 to 133 mm Hg and the mean diastolic blood pressure, from 89 to 78 mmHg (p < 0.0001, for both). Further, the mean blood pressure decreased (p < 0.0001), without any significant change in the pulse rate. Urinary protein excretion adjusted for urinary creatinine was reduced from 3,749 to 2,474 mg/g creatinine (p < 0.0001). No significant change was detected in the estimated glomerular filtration rate and serum creatinine level. With the switching from high-dose ARBs to the combination of normal-dose telmisartan and low-dose HCTZ treatment, the blood pressure decreased in all the subjects, and 36% of all the subjects achieved optimal blood pressure levels. No adverse metabolic effects were noted even among the diabetic patients. The monthly drug costs were significantly reduced after the switch (13,614 +/- 6,108 vs. 9,936 +/- 5,571 yen/month, p < 0.0001). We concluded that the telmisartan and HCTZ combination may be more efficacious than monotherapy of the high-dose ARBs in reducing blood pressure and urinary protein excretion in hypertensive patients with CKD. Further investigation would be required to assess whether the combination of high-dose ARBs and low-dose HCTZ has a greater antiproteinuric effect than the combination of normal-dose telmisartan (40 mg) and low-dose HCTZ (12.5 mg).

The Effect of High-Dose Valsartan on Left Ventricular Function Following Primary Percutaneous Coronary Intervention

REFER TO THE PAGE 77-83 The study by Kim et al.1) revealed that while improvement of regional function by valsartan was more effective in the high-dose (160 or 320 mg) valsartan group, compared with the low-dose group, high-dose valsartan did not have effects on left ventricular ejection fraction (LVEF) and lift ventriculal (LV) size. Angiotensin-receptor blockers (ARBs) should be used in post-ST-segment elevation myocardial infarction (STEMI) patients with evidence of LV dysfunction who are intolerant to angiotensin-converting enzyme (ACE) inhibitors.2) ARBs reduce mortality and morbidity rates in patients with heart failure (HF) and reduced LVEF. Investigators of the Val-HeFT3) and CHARM4) trials reported that high doses of ARBs improved clinical outcomes. Recently, the HEAAL study5) demonstrated that high-dose (losartan 150 mg) is superior to low-dose ARB (losartan 50 mg) in patients with HF and reduced LVEF. In contrast to the latter ARB trials, the VALIANT study6) focused on patients with HF after acute myocardial infarction (MI) and demonstrated that a high-dose ARB (valsartan 320 mg) was not inferior to an ACE inhibitor (captopril 150 mg). However, the VALIANT study did not evaluate dose-dependent clinical outcomes. The study by Kim et al.1) is helpful to understand changes in dose-dependent LV remodeling. However, this study has several limitations in terms of dose-dependent echocardiographic changes. First, the study population size was too small to compare LVEF and LV size between two groups. In the VALIANT Echo study, the small improvement in LVEF was observed in 610 patients. Second, baseline LVEF was too high (mean EF 52.7 ± 8.1%) to evaluate LV remodeling, compared to other remodeling studies such as the VALIANT (EF ≤ 35%) and HEAAL (EF ≤ 40%) studies. Third, the results do not definitively answer the question of why improvement of segmental wall motion was better in the high-dose than in the low-dose group. If additional information, such as myocardial microcirculation by myocardial contrast echocardiography and drugs affecting LV function were provided, the results would be more convincing. Valsartan (Diovan) is an oral angiotensin II-receptor antagonist with specificity for the angiotensin II type 1 receptor subtype. It has been shown to attenuate the progression of chronic HF and to reduce mortality in patients with myocardial infarction. Although based on clinical trials high-dose ARB (Valsartan 160 mg BID) is recommended for the improvement of LV function in heart failure, low-dose ARB is preferred in clinical practice in patients with HF. The ARB dose may vary according to race and personal preferences. In the VALIANT study, discontinuation of valsartan (160 mg BID) was observed in 1,675 (34%) patients. However, in the study by Kim et al.1), discontinuation of high-dose valsartan was seen in 43 (68%) patients. By comparing two groups prospectively after randomization, the present study concludes that high-dose valsartan is more effective than low-dose valsartan in improving segmental wall motion. Even though this is a small study to compare dose-dependent echocardiographic LV remodeling, it reveals the benefit of high-dose treatment, which may allow recommendation of high-dose valsartan even in post-STEMI cases.