Showing papers by "Joseph L. Izzo published in 2011"

Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes

Abstract: A b s t r ac t Background Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. Methods In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting–enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. Results The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P = 0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events — 81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P = 0.37) — but a greater number had fatal cardiovascular events — 15 patients (0.7%) as compared with 3 patients (0.1%) (P = 0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P = 0.02). Conclusions Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.)

Adherence and persistence with taking medication to control high blood pressure

Abstract: Nonadherence and poor or no persistence with taking antihypertensive medications results in uncontrolled high blood pressure, poor clinical outcomes and preventable health care costs. Factors associated with nonadherence are multilevel and relate not only to the patient, but also to the provider, health care system, health care organization, and community. National guideline committees have called for more aggressive approaches to implement strategies known to improve adherence and technologies known to enable changes at the systems level including improved communication among providers and patients. Improvements in adherence and persistence are likely to be achieved by supporting patient self-management, a team approach to patient care, technology-supported office practice systems, better methods to measure adherence, and less clinical inertia. Integrating high blood pressure control into health care policies that emphasize and improve prevention and management of chronic illness remains a challenge. Four strategies are proposed: focusing on clinical outcomes; empowering informed, activated patients; developing prepared proactive practice teams; and advocating for health care policy reform. With hypertension remaining the most common reason for office visits, the time is now.

Angiotensin-converting enzyme inhibitors.

Abstract: J Clin Hypertens (Greenwich). 2011;13:667–675. ©2011 Wiley Periodicals, Inc. Key Points and Recommendations • In addition to hypertension, angiotensin-converting enzyme inhibitors are indicated for treatment of patients at high risk for coronary artery disease, after myocardial infarction, with dilated cardiomypathy, or with chronic kidney disease. • The most familiar angiotensin-converting enzyme subtype, angiotensin-converting enzyme-1 (kininase II), cleaves the vasoconstrictor octapeptide angiotensin II from its inactive decapeptide precursor, angiotensin I, while simultaneously inactivating the vasodilator bradykinin. • Biochemical pathways within and around the renin-angiotensin system are highly species-specific; there is little evidence that “angiotensin-converting enzyme bypass pathways” have major clinical implications in humans. • Dietary sodium loading can diminish or abolish the antihypertensive effect of an angiotensin-converting enzyme inhibitor, while salt restriction or concomitant diuretic therapy enhances it. • Dose-response curves with angiotensin-converting enzyme inhibitors are quite flat but their peak effects vary in different individuals. • Increased serum creatinine (decreased glomerular filtration rate) during acute or chronic angiotensin-converting enzyme inhibition identifies individuals likely to experience long-term renal protective benefits. • Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy due to fetal toxicity. • Use of angiotensin-converting enzymes can be limited by idiosyncratic reactions (cough or angioedema), hyperkalemia (usually in cardiac or renal failure or with combined renin-angiotensin blockade) or hypotension (usually with severe volume-depletion or cardiac failure).

24-Hour Efficacy and Safety of Triple-Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: The TRINITY Ambulatory Blood Pressure Substudy

Abstract: This 12-week, multicenter, randomized, double-blinded, 4-arm study in 440 patients with moderate to severe hypertension compared ambulatory blood pressure (ABP) responses with a triple-combination regimen (olmesartan medoxomil [OM] 40 mg, amlodipine besylate [AML] 10 mg, and hydrochlorothiazide [HCTZ] 25 mg) and its component dual-combination regimens at similar doses. At week 12, the triple combination resulted in a greater reduction in mean 24-hour systolic and diastolic blood pressure (-30.3/-18.0 mm Hg) compared with the 3 dual-combination regimens (OM 40 mg/AML 10 mg: -23.5/-13.9, OM 40 mg/HCTZ 25 mg: -23.9/-14.5, and AML 10 mg/HCTZ 25 mg: -18.5 mm Hg/-10.7 mm Hg; P<.0001 each). Greater efficacy was also found during daytime and nighttime hours and during the last 6, 4, or 2 hours of the dosing interval. The authors conclude that the triple combination of OM 40 mg/AML 10 mg/HCTZ 25 mg demonstrated superior efficacy and sustained reductions in ABP compared with its dual-combination components.

Hypertension in diverse populations: a New York State Medicaid clinical guidance document.

Abstract: The New York State Medicaid Prescriber Education Program (PEP) is a partnership between the Department of Health and state academic institutions that provides prescribers with an evidence-based, noncommercial source of the latest objective information about pharmaceuticals. This article, detailing treatment of uncomplicated hypertension in diverse populations, represents one of the first large-scale PEP initiatives. The main risk factors for hypertension are age and obesity. Disparities in hypertension risk and outcomes among diverse populations are now believed to be more a function of personal habits, socioeconomic status and psychosocial factors rather than race, ethnicity, or genetics. Blood pressure is controllable in most patients, and all patients should be treated according to best practices. Lifestyle modification, especially diet and exercise, should be encouraged, but most patients will require more than one antihypertensive medication to control blood pressure. Combination therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker plus thiazide-type diuretic or dihydropyridine calcium channel blocker is largely universal in efficacy. Improved provider-patient partnership and communication is important to blood pressure lowering success, and cultural sensitivity should be taken into account where applicable.

The relationship between renal impairment and left ventricular structure, function, and ventricular–arterial interaction in hypertension

Abstract: ObjectivesOur objective was to define the relationship between renal dysfunction – both albuminuria and reduced estimated glomerular filtration rate (eGFR) – and cardiac structure and diastolic dysfunction among patients with chronic hypertension.MethodsBoth albuminuria and eGFR were measured in 540

Comparative efficacy and safety of combination aliskiren/amlodipine and amlodipine monotherapy in African Americans with stage 2 hypertension.

Abstract: Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

Treating systolic hypertension in the very elderly with valsartan-hydrochlorothiazide vs. either monotherapy: ValVET primary results.

Abstract: J Clin Hypertens (Greenwich). 2011;13:722–730. ©2011 Wiley Periodicals, Inc. This 16-week trial investigated the efficacy and safety of single-pill valsartan/hydrochlorothiazide (HCTZ) vs the individual components in patients 70 years and older with systolic hypertension. Patients were randomized to valsartan/HCTZ 160/12.5 mg (n=128), HCTZ 12.5 mg (n=128), or valsartan 160 mg (n=128) for 4 weeks. Patients whose blood pressure (BP) was ≥140/90 mm Hg at weeks 4, 8, or 12 were up-titrated to a maximum of valsartan/HCTZ 320/25 mg. Week 4 systolic BP reduction (primary efficacy outcome) was greater with valsartan/HCTZ than valsartan (−17.3 mm Hg vs −8.6 mm Hg, P <.0001) but only marginally greater than HCTZ (−13.6 mm Hg, P =.096). Median time to BP control was shorter with valsartan/HCTZ (4 weeks) vs HCTZ (8 weeks, P<.05) or valsartan (12 weeks, P<.0001). Thiazide monotherapy was more effective than angiotensin receptor blocker monotherapy (by about 5 mm Hg), but greater antihypertensive efficacy was achieved by initiating treatment with combination valsartan/HCTZ in the elderly.

Comparative efficacy and safety of combination aliskiren/amlodipine and amlodipine monotherapy in African Americans with stage 2 hypertension and obesity or metabolic syndrome

Abstract: The renin-angiotensin system (RAS) is a common link between hypertension and comorbidities of obesity and metabolic syndrome (MetS). We evaluated the antihypertensive efficacy and safety of the combination direct renin inhibitor, aliskiren, with amlodipine versus amlodipine alone in self-identified African Americans with stage 2 hypertension in a subgroup of patients with obesity or MetS participating in the Aliskiren Amlodipine Combination in African AmEricans with Stage 2 HypertenSion (AACESS) trial. Subjects, newly diagnosed and treatment naive or taking three or fewer antihypertensive drugs with a mean sitting systolic blood pressure (msSBP) of 160–199 mm Hg were randomized to receive aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week; force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg, for an additional 7 weeks. Overall, 292 obese (body mass index ≥30 kg/m 2 ) and 197 MetS subjects had baseline msSBP ranging from 167.0 to 167.5 mm Hg. Least-square mean reductions from baseline to 8 weeks in msSBP, the primary efficacy variable, were significantly higher with aliskiren/amlodipine than with amlodipine in both obese (−33.7 mm Hg vs. −27.9 mm Hg; P P

Effect of valsartan, hydrochlorothiazide, and their combination on 24-h ambulatory blood pressure response in elderly patients with systolic hypertension: a ValVET substudy.

Abstract: BACKGROUND Stage 2 hypertension often requires combination antihypertensive therapy. Ambulatory blood pressure monitoring (ABPM) is a useful tool for studying antihypertensive drugs and their combinations. OBJECTIVE This multicenter, double-blind, parallel-group, prompted-titration study of patients of at least 70 years of age with systolic hypertension compared the efficacy of valsartan, hydrochlorothiazide, and their combination on ambulatory blood pressure (ABP) reduction. METHODS After a 3-14-day washout, patients with systolic blood pressure of 150-200 mmHg were randomized (1 : 1 : 1) to initially receive once-daily valsartan/hydrochlorothiazide 160/12.5 mg combination therapy, hydrochlorothiazide 12.5 mg monotherapy, or valsartan 160 mg monotherapy. Prompted uptitration of patients in whom BP was more than or equal to 140/90 mmHg was performed after 4, 8, and 12 weeks of treatment. ABPM was performed at baseline and weeks 4 and 16 (study end). RESULTS In this ABPM substudy (n=108), initiation of treatment with valsartan/hydrochlorothiazide lowered ABP more effectively than either monotherapy throughout the daytime, night-time, and 24-h monitoring periods, as well as during the last 4 and 6-h dosing periods. Twenty-four-hour ABP was reduced from 141.1/76.5 mmHg at baseline to 125.8/69.2 mmHg at week 4 (primary time point) with valsartan/hydrochlorothiazide compared with reductions from 142.2/78.7 to 139.1/77.5 mmHg with hydrochlorothiazide and 142.2/78.3 to 136.4/75.1 mmHg with valsartan (all P<0.01 in favor of combination therapy). In the overall study, tolerability was similar among the three treatment groups. CONCLUSION In elderly hypertensives, starting combination therapy with valsartan/hydrochlorothiazide provides more effective 24-h blood pressure control than the monotherapy components, with few therapy-related side-effects.

Value of Angiotensin receptor blocker therapy in diabetes.

Abstract: There are more clinical trials investigating angiotensin receptor blockers (ARBs) in diabetes than any other drug class, ranging from early "prevention" trials to the treatment of individuals with advanced organ damage. In its earliest manifestations, visceral adiposity predisposes to hypertension and hyperglycemia (metabolic syndrome). In these individuals, ARB therapy delays the progression to chronic hypertension and may also delay the progression to overt diabetes. Based on the increased cardiovascular disease risk of the metabolic syndrome, which is similar to stage 1 hypertension, both lifestyle modification and ARB therapy are justifiable. ARB therapy has also been found to delay the onset of microalbuminuria and retinopathy. In established diabetic nephropathy, ARB therapy is recommended as a standard alternative to angiotensin-converting enzyme inhibition to reduce macroalbuminuria and delay the progression to end-stage disease. Finally, large trials in ischemic heart disease, heart failure, and stroke have demonstrated clear benefits of ARB therapy. Because ARBs have side effect rates equal to placebo and far lower than any other antihypertensive drug class, the benefit/risk ratio is highly favorable across the entire spectrum of diabetic disease. Thus, ARB therapy is a highly attractive alternative for individuals at any stage of diabetes and with any pattern of complications.

Combined aliskiren-amlodipine treatment for hypertension in African Americans: clinical science and management issues.

Abstract: While it may seem at first that antihypertensive drug combinations run counter to the desire to ‘personalize’ the management of hypertension, the best combinations have predictable efficacy in different individuals and subpopulations. Race is probably not a valid surrogate for clinically meaningful genetic variation or guide to therapy. Most guidelines suggest similar blood pressure goals for different races but drug treatment recommendations have diverged. In the United States, race is not considered to be a major factor in drug choice, but in England and other countries, initial therapy with renin–angiotensin system blocking drugs is not recommended in Blacks. In this review we: (1) examine new trends in race-based research; (2) emphasize the weaknesses of race-based treatment recommendations; and (3) explore the effects of a new combination, renin inhibition (aliskiren) and amlodipine, in African Americans.

Combination therapy with aliskiren and amlodipine in hypertension: treatment rationale and clinical results

Abstract: Optimal antihypertensive therapy requires a multimodal approach based on lifestyle modification and, for most individuals, combination drug therapy. Recommendations from experts suggest that a combination of an agent that blocks the renin-angiotensin system (RAS), together with a vasodilator (generally a calcium-channel blocker or a thiazide-type diuretic), is most likely to control blood pressure and provide the widest overall cardiovascular protection. Understanding the opportunities afforded by the combination of RAS blockade with a calcium-channel blocker requires a discussion of basic and clinical science data. One new concept is that of 'global' or total RAS blockade. The impact of the RAS can be diminished or blocked by several different classes of drugs (central sympatholytics, β-blockers, renin inhibitors, ACE inhibitors or ARBs); what is most important is how effectively the overall impact of angiotensin II is blunted. A second new concept is that the complementary actions of RAS blockers and calcium-channel blockers are best explained on the basis of diminished intracellular calcium availability in excitable tissue (sympathetic neurons and vascular smooth muscle cells) via parallel actions that reduce angiotensin II type-1 receptor stimulation and L-channel-mediated calcium flux. Aliskiren is the first of the direct renin inhibitors, the newest subclass of RAS blockers. In both short- and long-term studies, aliskiren has been shown to be similar in efficacy and tolerability compared with other RAS blockers, with the added benefit that its effects persist longer. Outcome studies with aliskiren are currently underway.

Benefits of antihypertensive drugs when blood pressure is below 140/90 mmHg.

Abstract: Antihypertensive medications are used to lower blood pressure (BP) but, ultimately, their true value lies in reductions in morbidity and mortality (cardiovascular, cerebrovascular, and renal diseases). Hypertension is defined discreetly (generally 140/90 mmHg) but the actual relationship between BP and adverse cardiac and cerebrovascular outcomes is continuous. Observational studies have demonstrated a powerful log-linear relationship between BP and mortality due to ischemic heart disease (IHD) or stroke over the range of 115/75 to 185/115 mmHg. Clinical trials and meta-analyses have clearly demonstrated benefits of antihypertensive drugs in nonhypertensive individuals: delay or prevention of the onset of hypertension and microalbuminuria and reduced morbidity and mortality from IHD, stroke, and chronic kidney disease. This is not surprising given that various antihypertensive drug classes have multiple potential beneficial effects. A persistent concern is that overtreatment of hypertension may increase risk in individuals with coronary artery disease, but a "J-curve" effect is not consistently found in clinical studies. The use of antihypertensive drugs in at-risk individuals who are below the traditional threshold (140/90 mmHg) is fully justifiable, but the decision requires adequate clinical experience and judgment and a full assessment of risks and benefits.

Office and ambulatory pulse pressure--association with clinical characteristics and cardiovascular risk factors in normoalbuminuric patients with type 2 diabetes (ROADMAP study).

Abstract: To investigate the association of office and ambulatory 24-h pulse pressure (PP) with clinical characteristics and cardiovascular risk factors in normoalbuminuric type 2 diabetic patients enrolled to the Randomised Olmesartan and Diabetes Microalbuminuria Prevention study, 4449 patients (2054 male and 2395 female; mean age 57.7±8.7 years) with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor were included into the analysis. After adjustment by age, there were significant correlations between office PP and presence of hypertension (r=0.24; P<0.001), presence of cardiac and vascular disorders (r=0.17; P<0.001), metabolic syndrome (r=0.10; P<0.001), duration of diabetes (r=0.09; P<0.001), fasting blood glucose (r=0.08; P<0.001), albumin/creatinine ratio (r=0.07; P<0.001), insulin treatment, glycosylated haemoglobin (HbA1c), male gender and current smoking. In the subgroup of 1234 patients with ambulatory blood pressure measurement performed, ambulatory PP adjusted for office PP correlated with fasting blood glucose (r=0.16; P<0.001), metabolic syndrome (r=0.14; P<0.001), albumin/creatinine ratio (r=0.11; P<0.001) and indices of glycemic control (HbA1c: r=0.11; P<0.001). In this group of normoalbuminuric type 2 diabetic patients, office and ambulatory PP were associated with duration of diabetes, indices of glycemic control and cardiovascular risk factors. There was relationship between office and ambulatory PP and albuminuria even within normal albuminuria range.