Firibastat: a Novel Treatment for Hypertension.

PURPOSE OF REVIEW: The purpose of this review is to discuss the unique mechanism of firibastat, a new antihypertension medication. Hypertension continues to be a highly prevalent public health issue. RECENT FINDINGS: Firibastat is a novel agent developed to treat hypertension. As the first member in the class of centrally acting agents to target the brain renin angiotensin system, firibastat offers new pathways to consider and enhances the regimen of agents currently available to treat hypertension. Recent clinical trials have demonstrated effectiveness and safety in mild hypertension as well as resistant hypertension. This review introduces firibastat as a new therapeutic class of treatment for hypertension focused on the renin angiotensin system in the brain. Early studies have shown a significant reduction in blood pressure with minimal side effects particularly in patients who are difficult to treat.

Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins.

BACKGROUND: Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population. METHODS: Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP) >140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety. RESULTS: Firibastat lowered systolic AOBP by 9.5 mm Hg ( P<0.0001) and diastolic AOBP by 4.2 mm Hg ( P<0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all subgroups regardless age, sex, body mass index, or race. Systolic AOBP decreased by 10.2 mm Hg ( P<0.0001) in obese patients, by 10.5 mm Hg ( P<0.0001) in blacks, and 8.9 mm Hg ( P<0.0001) in nonblacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium, and creatinine blood level were observed. CONCLUSIONS: Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03198793.

Social, Racial, and Cultural Considerations in Hypertension in Older Adults.

Black and Hispanic older adults in the United States have higher prevalence of hypertension, less adequate treatment, less consistent blood pressure control, and worse cardiovascular outcomes than their white counterparts. Genetic differences are insufficient to explain these disparities-various social, economic, and environmental factors notably contribute. Racial and ethnic differences in living circumstances, household income, access to appropriate care, food security, educational attainment, and tobacco use all negatively impact long-term hypertension outcomes in minoritized older adults. To remedy these inequities, the search for solutions must include a complete assessment of the social, racial, and cultural components of the problem.

Feasibility of treating prehypertension with an angiotensin-receptor blocker.

BACKGROUND: Prehypertension is considered a precursor of stage 1 hypertension and a predictor of excessive cardiovascular risk. We investigated whether pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension. METHODS: Participants with repeated measurements of systolic pressure of 130 to 139 mm Hg and diastolic pressure of 89 mm Hg or lower, or systolic pressure of 139 mm Hg or lower and diastolic pressure of 85 to 89 mm Hg, were randomly assigned to receive two years of candesartan (Atacand, AstraZeneca) or placebo, followed by two years of placebo for all. When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated. Both the candesartan group and the placebo group were instructed to make changes in lifestyle to reduce blood pressure throughout the trial. RESULTS: A total of 409 participants were randomly assigned to candesartan, and 400 to placebo. Data on 772 participants (391 in the candesartan group and 381 in the placebo group; mean age, 48.5 years; 59.6 percent men) were available for analysis. During the first two years, hypertension developed in 154 participants in the placebo group and 53 of those in the candesartan group (relative risk reduction, 66.3 percent; P<0.001). After four years, hypertension had developed in 240 participants in the placebo group and 208 of those in the candesartan group (relative risk reduction, 15.6 percent; P<0.007). Serious adverse events occurred in 3.5 percent of the participants assigned to candesartan and 5.9 percent of those receiving placebo. CONCLUSIONS: Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients with untreated prehypertension (the placebo group). Treatment of prehypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period. Thus, treatment of prehypertension appears to be feasible. (ClinicalTrials.gov number, NCT00227318.).

An evaluation of the effects of an angiotensin receptor blocker on health-related quality of life in patients with high-normal blood pressure (prehypertension) in the Trial of Preventing Hypertension (TROPHY).

The Trial of Preventing Hypertension (TROPHY) demonstrated the feasibility of possibly reducing the incidence of hypertension with the angiotensin receptor blocker candesartan compared with placebo. The long-term benefits of pharmacologic therapy in high-normal blood pressure, or prehypertension are not known, and the long-term effect on health-related quality of life (HRQL) has not been determined. An analysis of covariance model was used to assess treatment differences from baseline in the HRQL scores using Short Form (SF)-36, and component measures at subsequent visits. Of the 809 randomized patients, 734 had both baseline and > or =1 HRQL follow-up assessment: 95% (379 of 397) of patients receiving candesartan and 91% (355 of 388) of patients receiving placebo. There were no statistically significant between-group differences in least-squares mean physical component survey and mental component survey scores or the individual scales at each scheduled visit relative to baseline values (P >.05). In TROPHY, patients with prehypertension had relatively high baseline HRQL, and HRQL was maintained with the angiotensin receptor blocker candesartan over both the 2-year treatment period and a total 4-year trial period.

Measurement of 18-hydroxycorticosterone during adrenal vein sampling for primary aldosteronism.

CONTEXT: In primary aldosteronism, elevated serum 18-hydroxycorticosterone (18OHB) suggests aldosterone-producing adenoma (APA) rather than bilateral, idiopathic hyperaldosteronism (IHA), but little is known about the relative production of 18OHB and aldosterone (A) in APAs compared with IHA. OBJECTIVES: We measured 18OHB, A, and cortisol (F) in blood from adrenal vein sampling (AVS) studies. We compared the discriminatory power of gradients in 18OHB/A and 18OHB/F ratios with A/F ratio gradients for distinguishing APA from IHA. DESIGN, SETTING, AND SUBJECTS: We measured 18OHB and A in excess serum from 23 AVS studies performed at our university hospitals. MAIN OUTCOME MEASURES: We calculated the ratios 18OHB/A, 18OHB/F, and A/F for all specimens, and determined the adrenal vein gradients for these ratios. RESULTS: The 18OHB/A ratios were much lower in blood draining APAs (2.17 +/- 0.62) than in blood draining the contralateral adrenals (12.96 +/- 12.76; P < 0.001) but similar to blood draining IHA adrenals (4.69 +/- 4.32; P = 0.02). In contrast, the 18OHB/F ratios were elevated in specimens from APAs (26.03 +/- 11.51) compared with IHA adrenals (9.22 +/- 5.18; P < 0.001) or the contralateral adrenals (6.23 +/- 2.97; P < 0.001). Using 18OHB/F gradient greater than two or 18OHB/A gradient less than 0.5 as criteria for lateralization, interpretations agreed with lateralizations based on A/F gradients in 21 of 23 cases. CONCLUSIONS: High serum 18OHB in APA reflects augmented production of both 18OHB and A, not disproportionate 18OHB secretion relative to A. The 18OHB/A and 18OHB/F gradients are useful adjuncts but not as reliable as A/F gradients for A lateralization during AVS.

Antihypertensive combination therapy: optimizing blood pressure control and cardiovascular risk reduction.

Treating hypertension reduces the rates of myocardial infarction, stroke, and renal disease; however, clinical trial experience suggests that monotherapy is not likely to be successful for achieving goal blood pressure (BP) levels in many hypertensive patients. In multiple recent clinical trials including various subsets of hypertensive patients, the achievement of BP goal has typically required the combination of 2 or more medications, particularly in patients with BP levels>160/100 mm Hg. When initiating combination therapy for hypertension, careful consideration must be given to the choice of medication. Clinical trial evidence has shown the efficacy of various combinations of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics in reducing BP and cardiovascular risk. Ongoing trials should provide additional guidance on the optimal choice of combination regimens in specific clinical settings.

Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.

OBJECTIVE: Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. METHODS: In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. RESULTS: Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mmHg x min x 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 l/kg x mmol x min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg x min x 100 and 12.6 versus 11.1 l/kg x mmol x min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus -14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = -0.16, P < 0.05) independently of the relative change in body mass index (r = -0.29, P < 0.001). CONCLUSIONS: As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.

Hypertension in special populations.

Hypertension is a multifaceted disease that may present somewhat differently in various populations. It is clear that hypertensive treatment reduces cardiovascular, renal, and cerebrovascular outcomes for all patients, yet recent clinical trial data suggest that some groups may benefit more than others from specific drug intervention. Furthermore, these data justify specific approaches for some special populations. This article reviews important features of the presentation, rationale for treatment, and treatment recommendations for the treatment of hypertension in special populations. The special populations addressed include diabetic patients, the elderly, and women.

Is low-risk hypertension fact or fiction? cardiovascular risk profile in the TROPHY study.

BACKGROUND: The Trial of Preventing Hypertension (TROPHY) Study is designed to establish whether treating high normal blood pressure with a low-dose angiotensin receptor blocker, candesartan cilexetil, for 2 years reduces the rate of progression to hypertension compared with placebo treatment over a 4-year observation period. We are presenting the baseline cardiovascular risk factor profile of the 809 subjects randomized in the TROPHY Study. The risk factors in this analysis were as follows: cholesterol >or=200 mg/dl; LDL-cholesterol >or=160 mg/dL; HDL-cholesterol or=150 mg/dL; body mass index >or=25 kg/m2 (overweight and obese), fasting insulin >or=20 mU/mL; heart rate >or=80 beats/min; hematocrit >or=43.5 % (men) and >or=41.2% (women). METHODS: The TROPHY Study is a 4-year randomized, placebo-controlled, multicenter clinical trial of 809 subjects with high normal blood pressure (BP), which is currently in progress. RESULTS: The participants of the TROPHY study (mean age 49+/-8.1 years) with high normal BP (mean 134+/-4/85+/-4 mm Hg) had additional cardiovascular risk factors. Of the group, 96% had at least one, 81% had two or more, and 13% had five or more additional risk factors. CONCLUSIONS: Our data from individuals with high normal BP suggests clearly that the risk of cardiovascular disease begins to rise before the diagnosis of hypertension is evident. The overall risk in such subjects reflects both the rising BP and other concurring factors. It appears that truly low-risk hypertension only rarely exists.

Overweight as a risk factor in children: a focus on ethnicity.

The prevalence of overweight in youth is increasing dramatically in the United States. The intimate relationship of obesity and overweight with cardiovascular risk factors and diabetes in adults raises concern for the likelihood of subsequent disease development in children. Ethnic minorities are so disproportionately affected by overweight that a call to action is necessary. The International Society on Hypertension in Blacks convened this work group as part of a larger effort to focus on cardiovascular risk protection beginning in childhood and adolescence, entitled the "Children are Our Messengers: Changing the Health Message" initiative. This summary article reviews the data on cardiovascular risk factors and overweight in ethnic children and adolescents, and culminates in a practical algorithm for evaluating overweight children for cardiovascular risk.

In prehypertension leukocytosis is associated with body mass index but not with blood pressure or incident hypertension.

BACKGROUND: Previous studies reported increased white blood cell counts (WBCCs), an inflammatory marker, in hypertension, prehypertension and metabolic syndrome. Evidence suggests that inflammation precedes blood pressure (BP) elevation and may contribute to incident hypertension. Angiotensin receptor blockers (ARBs) may reduce inflammation. We analyzed WBCC trends in TRial Of Preventing HYpertension (TROPHY) to determine if this inflammatory marker predicted incident hypertension in prehypertensive individuals and whether randomized assignment to the ARB candesartan (391 individuals) for 2 years, lowered WBCC compared with placebo-treated controls (381 individuals). METHODS: A new analysis of TROPHY trial data. RESULTS: In the total population, baseline BMI correlated with WBCC (r = 0.185, P < 0.0001), neutrophils (r = 0.135, P < 0.001) and lymphocytes (r = 0.204, P < 0.0001). Baseline triglycerides also correlated significantly with inflammatory markers. Despite a wide range of home BP (HBP) values, HBP did not correlate with baseline WBCC counts. After 2 years, candesartan decreased placebo corrected HBP by -5.5/-2.5 mmHg, (P < 0.0001), but WBCC, neutrophil and lymphocyte counts were not different in placebo and in candesartan groups. Baseline WBCC, neutrophils and lymphocyte counts did not predict incident hypertension in the placebo group. CONCLUSION: In TROPHY, candesartan lowered BP but did not alter WBCC. Baseline WBCC did not predict incident hypertension. Our findings do not support the hypothesis that inflammation contributes to incident hypertension or that ARB treatment suppresses inflammation. The significant independent association of WBCC with baseline BMI and triglycerides is consistent with the evidence that obesity and insulin resistance are associated with inflammation. The findings highlight the importance of effective lifestyle modification in prehypertension to reduce inflammatory cardio-metabolic risk and suppress transition to hypertension.

A titrate-to-goal study of switching patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations of amlodipine and olmesartan medoxomil ± hydrochlorothiazide.

In the prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6 ± 11.4 years; baseline blood pressure [BP], 153.7 ± 9.2/91.9 ± 8.6 mm Hg) were switched to fixed-dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP < 140 mm Hg (< 130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (± standard error) BP changes from baseline during the titration periods ranged from -14.2±0.4 mm Hg/-7.7 ± 0.3 mm Hg for AML/OM 5/20 mg to -25.1 ± 0.7 mm Hg/-13.7 ± 0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24-hour efficacy was maintained. Treatment-emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug-related TEAEs occurred in 255 patients (25.5%). This well-tolerated, treat-to-goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single-pill AML/OM combination therapy or triple therapy with the addition of HCTZ. .

Overcoming therapeutic inertia in patients with hypertension.

Uncontrolled blood pressure (BP) remains a leading contributor to cardiovascular disease and mortality worldwide. Although current practice guidelines recommend treating patients with hypertension to defined BP goals, the approach is not widely implemented, and BP control in clinical practice is much worse than that attained in clinical trials. Recent and ongoing clinical trials are utilizing more aggressive approaches with combination therapy as initial treatment. This article discusses the problem of therapeutic or clinical inertia when attempting to control hypertension and highlights differences in BP control rates between clinical trials and real-world practice. Additionally, the rationale for an ongoing treat-to-goal study using a fixed-dose combination of amlodipine/olmesartan medoxomil in patients with hypertension not controlled on monotherapy is provided.

Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism.

CONTEXT: Aldosterone has been shown to exert a central sympathoexcitatory action in multiple animal models, but evidence in humans is still lacking. OBJECTIVES: Our objective was to determine whether hyperaldosteronism causes reversible sympathetic activation in humans. METHODS: We performed a cross-sectional comparison of muscle sympathetic nerve activity (SNA, intraneural microelectrodes) in 14 hypertensive patients with biochemically proven primary aldosteronism (PA) with 20 patients with essential hypertension (EH) and 18 age-matched normotensive (NT) controls. Seven patients with aldosterone-producing adenoma (APA) were restudied 1 month after unilateral adrenalectomy. RESULTS: Mean blood pressure values in patients with PA and EH and NT controls was 145 ± 4/88 ± 2, 150 ± 4/90 ± 2, and 119 ± 2/76 ± 2 mm Hg, respectively. The major new findings are 2-fold: 1) baseline SNA was significantly higher in the PA than the NT group (40 ± 3 vs. 30 ± 2 bursts/min, P = 0.014) but similar to the EH group (41 ± 3 bursts/min) and 2) after unilateral adrenalectomy for APA, SNA decreased significantly from 38 ± 5 to 27 ± 4 bursts/min (P = 0.01), plasma aldosterone levels fell from 72.4 ± 20.3 to 11.4 ± 2.3 ng/dl (P < 0.01), and blood pressure decreased from 155 ± 8/94 ± 3 to 117 ± 4/77 ± 2 mm Hg (P < 0.01). CONCLUSION: These data provide the first evidence in humans that APA is accompanied by reversible sympathetic overactivity, which may contribute to the accelerated hypertensive target organ disease in this condition.

Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement.

Since the first International Society on Hypertension in Blacks consensus statement on the "Management of High Blood Pressure in African American" in 2003, data from additional clinical trials have become available. We reviewed hypertension and cardiovascular disease prevention and treatment guidelines, pharmacological hypertension clinical end point trials, and blood pressure-lowering trials in blacks. Selected trials without significant black representation were considered. In this update, blacks with hypertension are divided into 2 risk strata, primary prevention, where elevated blood pressure without target organ damage, preclinical cardiovascular disease, or overt cardiovascular disease for whom blood pressure consistently <135/85 mm Hg is recommended, and secondary prevention, where elevated blood pressure with target organ damage, preclinical cardiovascular disease, and/or a history of cardiovascular disease, for whom blood pressure consistently <130/80 mm Hg is recommended. If blood pressure is ≤10 mm Hg above target levels, monotherapy with a diuretic or calcium channel blocker is preferred. When blood pressure is >15/10 mm Hg above target, 2-drug therapy is recommended, with either a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous and/or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker. Effective multidrug therapeutic combinations through 4 drugs are described. Comprehensive lifestyle modifications should be initiated in blacks when blood pressure is ≥115/75 mm Hg. The updated International Society on Hypertension in Blacks consensus statement on hypertension management in blacks lowers the minimum target blood pressure level for the lowest-risk blacks, emphasizes effective multidrug regimens, and de-emphasizes monotherapy.