Amlodipine/Valsartan in Non-Whites With Hypertension
Amlodipine/Valsartan in Non-Whites With Hypertension
Results of several studies suggest that some RAASblocking drugs manifest diminished average BP responses in black patients relative to other drug classes (i.e., calcium channel blockers, thiazide diuretics). However, the use of multiple antihypertensive agents has been shown to offset any racial/ethnic differences in response to therapy. Moreover, RAAS pharmacological blockade provides greater cardiorenal protection than other non-RAAS drug classes. A major renoprotective effect is demonstrated with ramipril in African Americans with hypertensive nephropathy, a group at risk for more rapid loss of kidney function over time. Hispanics/Latinos and Asians with hypertension are also likely to benefit from the use of RAAS inhibitors, especially given that these patients pose a challenge to BP control secondary to their high prevalence of other cardiovascular risk factors such as obesity, diabetes, and metabolic syndrome. Thus, there is a good rationale for the use of RAAS inhibitors as foundation therapy in these high-risk patients, with diuretic or calcium channel blocker added as needed.
Dihydropyridine calcium channel blockers and angiotensin receptor blockers have complementary mechanisms of action (Fig. 1), and each of these drug classes is recommended in the prevention and/or treatment of most complications of hypertension (Fig. 2). The following sections and Table 1 summarize the results of studies with combination amlodipine/valsartan in non-white populations with hypertension, with a focus on blacks, Hispanics/Latinos, and Asians. Since these drugs are widely utilized in the USA in hypertension pharmacotherapy, these particular agents, representing the dihydropyridine calcium channel blocker and angiotensin receptor blocker drug classes, will be the main focus of discussion. Both valsartan and amlodipine have been extensively studied, with a wealth of BP and outcomes data.
(Enlarge Image)
Figure 1.
Complementary mechanisms of action (MOA) of dihydropyridine calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) in lowering blood pressure (BP). Reprinted from Neutel [47], with permission from JTE Multimedia
(Enlarge Image)
Figure 2.
Conditions favoring the use of dihydropyridine calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) according to guidelines for the management of hypertension. Reprinted with permission of Dove Medical Press Ltd, from Waeber and Ruilope [48]; permission conveyed through Copyright Clearance Center, Inc
A search of PubMed was conducted through to 25 February 2013, using the title/abstract key words (amlodipine AND valsartan AND [hypertension OR hypertensive] AND [black(s) OR African American(s) OR Hispanic(s) OR Latino(s) OR Mexican(s) OR Asian(s)]). This search revealed a total of 19 articles in the English language. A review of the abstracts from this search and/or safety evaluation of combination amlodipine/valsartan in the non-white populations of interest [42, 53–58]. The authors were aware of and included an additional study that was not identified in the PubMed search. In total, these studies comprised 1,111 black, 389 Hispanic/Latino, and 3,094 Asian patients with hypertension.
Even though hypertension hardly existed in black Africa in the first half of the 20th century, more recently, in those aged 65 years and over, hypertension has been shown to affect 30–60 % of African blacks. Moreover, this proportion is steadily approaching the 60–70 % range in the USA for blacks of similar age. Thus, reducing BP and controlling hypertension are critical factors in preventing CVD.
In the Newer versus Older Antihypertensive agents in African Hypertensive patients (NOAAH) trial, Odili and colleagues compared the BP-lowering efficacy of a combination of newer (without a diuretic) versus older (with a diuretic) antihypertensive agents in black patients with hypertension born and living in sub-Saharan Africa. The NOAAH study compared two SPCs for control of BP in African patients 30–69 years of age (mean age 51 years) with stage 1 or 2 hypertension (systolic/diastolic BP: 140–179/90–109 mmHg) and no more than two additional risk factors. After a 4-week wash-out period, 140 patients were randomized to once-daily bisoprolol/hydrochlorothiazide (HCTZ) 5/6.25 mg or amlodipine/valsartan 5/160 mg, with permitted up-titration of the bisoprolol and amlodipine doses to 10 mg to achieve BP<140/90 mmHg. At randomization, the bisoprolol/HCTZ and amlodipine/valsartan groups were similar with respect to demographic characteristics, and the overall combined systolic/diastolic BP was 153.9/91.5 mmHg. After randomization, in both groups combined, BP dropped by 18.2/10.1 mmHg at week 2 (n = 122), 19.4/11.2 mmHg at week 4 (n = 109), 22.4/12.2 mmHg at week 8 (n = 57), and 25.8/15.2 mmHg at week 12 (n = 49). The BP control rate of <140/90 mmHg was [65 % by week 2. Thus, NOAAH confirmed that SPC therapy can achieve BP control quickly in black patients born and living in sub-Saharan Africa and that randomized clinical trials of antihypertensive drugs in this indigenous population are feasible.
Although most studies have been done in blacks of African descent in the USA, there are data suggesting that an increase in the incidence of hypertension in blacks living in sub-Saharan Africa is leading to an increase in heart failure and CVD. In a recent (2012) study by Damasceno and colleagues, a prospective, multicenter, observational survey collected data on patients with acute heart failure (AHF) who had been admitted to 12 university hospitals in nine African countries (Sub-Saharan Africa Survey of Heart Failure [THESUS-HF]). The THESUS-HF survey enrolled 1,006 patients presenting with AHF between 2007 and 2010; mean age was 52.3 years, 50.8 % were women, the predominant race was black African (98.5 %), and mean left ventricular ejection fraction was 39.5 %. The most common reason for heart failure was noted to be hypertension (45.4 %), while rheumatic heart disease (14.3 %) and ischemic heart disease (7.7 %) were not as commonly documented causes of AHF. The median hospital stay was 7 days, with an in-hospital mortality of 4.2 % and an estimated 180-day mortality of 17.8 % (95 % confidence interval 15.4–20.6). Overall, the THESUS-HF survey demonstrated that in African patients, AHF is primarily due to a non-ischemic cause, most commonly hypertension; occurs equally among genders, usually in middle-aged adults; and is associated with high mortality.
The EXforge evaluation in Stage Two hypertensives of AfricaN Descent (EX-STAND) study was a 12-week, multicenter, double-blind, prospective, parallel-group trial of 572 black patients (mean age 53 years) with stage 2 hypertension (mean sitting systolic blood pressure [MSSBP] 160–199 mmHg) in the USA. Patients were randomized to either combination amlodipine/valsartan 5/160 mg or amlodipine 5-mg monotherapy. At 2 weeks, doses were force-titrated to 10/160 mg and 10 mg, respectively. At 4 weeks, there was optional up-titration to 10/320 mg in the combination-therapy arm if MSSBP was C130 mmHg. The combination of amlodipine/valsartan attained greater and faster reductions in BP: by week 8, combination amlodipine/valsartan significantly lowered MSSBP more than monotherapy (33.3 vs. 26.6 mmHg; P< 0.0001). A BP goal of<140/90 mmHg was achieved by 49.8 and 30.2 % of patients, respectively (P< 0.0001).
A subgroup analysis of two 8-week, multicenter, randomized, double-blind, placebo-controlled studies (n = 3,161) included 2,508 white patients (mean age 56 years) and 201 black patients (mean age 50 years) with stage 1 or 2 hypertension (mean sitting diastolic blood pressure [MSDBP] 95–109 mmHg). Patients received amlodipine monotherapy, valsartan monotherapy, or a combination of these agents at various dosages ( Table 1 ). Combination therapy was significantly more effective in lowering BP than treatment with the respective monotherapies. In blacks, the greatest reduction in MSDBP was seen with amlodipine/valsartan 5/320 mg (17.9 mmHg), which was consistent with the reduction seen in whites (15.5 mmHg).
In a post hoc analysis of patients with hypertension enrolled in a 12-week, multicenter, randomized, double-blind clinical trial (EXforge TaRget Achievement [EXTRA]), treatment responses with combination amlodipine/valsartan 10/320 mg versus amlodipine/valsartan 5/160 mg were evaluated among a diverse cohort (474 white, 198 black, and 165 Hispanic individuals ranging in age from a mean of 51–57 years). Patients were treatment naïve or nonresponders (MSSBP 150–199 mmHg) to angiotensin receptor blocker monotherapy (other than valsartan). Regardless of race or ethnic background, results demonstrated that more intensive dosage treatment provided greater BP lowering versus moderate treatment. In blacks, moderate treatment for 4 weeks (before addition of HCTZ) lowered MSSBP by 18.1 mmHg and allowed 26.9 % of patients to achieve BP goal (<140/90 mmHg), whereas intensive treatment lowered MSSBP by 20.4 mmHg with 37.1 %of patients attaining BP goal (P = not significant/P< 0.01). Further improvement in BP was seen with the addition of HCTZ.
Across all studies, the combination of amlodipine/valsartan was well tolerated ( Table 1 ). Peripheral edema was reported at an incidence ranging from 2.1 to 12.6 % in the black population, which was within the range reported in control patients (9.5–15.4 %). Other adverse events reported among blacks treated with amlodipine/valsartan included headache (3.2–6.1 vs. 5.3–7.7 % in controls) and dizziness (2.1–6.7 vs. 2.5 % in controls).
In the EXforge EFFicacy and Control in Treatment of Stage 2 hypertension (EX-EFFeCTS) study, the efficacy and safety of combination amlodipine/valsartan versus amlodipine alone were compared in 646 patients (mean age 58 years) with stage 2 hypertension (MSSBP 160–199 mmHg). In this 8-week, multicenter, randomized, double-blind study, approximately one third of the study population (n = 224; 34.7 %) was of Hispanic/Latino ethnicity. The initiating doses were amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks, with force-titration to amlodipine/valsartan 10/160 mg or amlodipine 10 mg, respectively, for an additional 6 weeks. At 4 weeks (primary endpoint), MSSBP demonstrated an improvement in Hispanic/Latino patients receiving amlodipine/valsartan compared with those receiving amlodipine alone (-29.1 vs. -23.0 mmHg; P< 0.05). An MSSBP<140 mmHg was achieved by 55.1 and 35.8 % of Hispanic/Latino patients, respectively (P value not reported).
The previously mentioned post hoc analysis by Ofili and colleagues included 165 (22.7 %) Hispanic patients. In this population, treatment with combination amlodipine/valsartan for 4 weeks lowered MSSBP by 17.5 mmHg (moderate treatment) or 23.4 mmHg (intensive treatment) (P< 0.01). Corresponding BP control rates were 33.3 and 54.8 % (P< 0.01). As in black people, the addition of HCTZ provided further antihypertensive efficacy.
In both of the above studies, efficacy results in Hispanic/Latino patients were similar to those seen for other race groups and the overall population ( Table 1 ). In addition, the combination of amlodipine/valsartan was well tolerated, providing support for use of this regimen in Hispanic/Latino patients. The most commonly reported adverse event was peripheral edema: 8.2 % with the intensive regimen and 2.5 % with the moderate regimen in one study and 12.8 % with combination therapy versus 17.6 % with amlodipine monotherapy in the other study. Across both studies, headache was reported by 2.4–4.9 % of patients receiving amlodipine/valsartan and 3.1 % of patients receiving amlodipine alone.
Due to less-robust data in Asian Americans, clinical data are discussed for non-American Asian cohorts. Recently, an open-label, observational, non-interventional, surveillance study was designed to evaluate the safety and effectiveness of the amlodipine/valsartan combination. There were 2,729 participants with systolic BP [140 mmHg and/or diastolic BP[90 mmHg from 298 centers around the world, including China, Malaysia, Pakistan, Bangladesh, Egypt, and Russia. The cohort was composed of 54.5 % men, 54.2 % Asian, and 44.6 % white. Mean age was 57.9 years, baseline BP was 163.1/96.2 mmHg, and 86.5 % had prior hypertension therapy that was discontinued. During the 12 weeks of treatment with amlodipine/valsartan, there was a significant systolic/diastolic BP reduction of 33.2/16.9 mmHg (P< 0.0001), resulting in a substantially lower final BP reading of 129.9/79.3 mmHg. Additionally, Chazova and colleagues demonstrated a dose-dependent effect with amlodipine/valsartan where the smallest BP reduction was 29.2/15.1 mmHg with the 5/80- mg dose (P< 0.0001) and the greatest BP reduction was 43.6/22.4 mmHg with the 10/160-mg dose (P< 0.0001). BP lowering was linked to the severity of baseline BP levels.
In an 8-week, multicenter, randomized, double-blind trial, Ke and colleagues studied the effects of the SPC of amlodipine/valsartan compared with amlodipine alone in an Asian hypertensive population that was non-responsive (MSDBP 90–109 mmHg) to amlodipine 5-mg monotherapy. Baseline characteristics were similar between treatment groups: the majority of patients were male (65.1 %) and Chinese (86.4 %); mean age was 53.8 years; and mean seated systolic/diastolic BP was 139.5/94.5 mmHg. After a 1–4-week washout period, a total of 698 patients were randomized to either amlodipine/valsartan 5/80 mg or amlodipine 5 mg. Results showed that the reduction in systolic/diastolic BP at the week 8 endpoint was significantly greater with amlodipine/valsartan than with amlodipine (11.4/9.7 vs. 7.4/7.1 mmHg; P< 0.0001), with a correspondingly higher BP-control rate (<140/90 mmHg): 69.2 versus 57.6 %; P = 0.0013.
Huang and colleagues evaluated the efficacy of the SPC of amlodipine/valsartan in another 8-week, randomized, double-blind study of 918 Asian patients (mean age 52 years) with stage 1 or 2 hypertension (MSDBP 90–109 mmHg) from 30 centers inAsiawhowere not responding to valsartan 80-mg monotherapy. The patients were randomized to receive amlodipine/valsartan 5/80 mg (n = 308), valsartan 80 mg (n = 307), or valsartan 160 mg (n = 303).Results at theweek 8 endpoint revealed reductions in BP of 12.5/10.8 mmHg for amlodipine/valsartan 5/80 mg, which were significantly greater than those for valsartan 80 mg (6.0/6.3 mmHg) or valsartan 160 mg (7.7/7.2 mmHg) (P< 0.0001). Regardless of baseline BP, at theweek 8 endpoint, a significant proportion of patients achieved BP control with amlodipine/valsartan 5/80 mgcompared with the valsartanmonotherapies (Table 1; P< 0.01 for both comparisons).
As shown in Table 1, the combination of amlodipine/valsartan was well tolerated across each of the above studies. Across the three studies identified in the Asian population assessments, the most commonly reported adverse event was hyperlipidemia (up to 4.3 % of patients on amlodipine/valsartan vs. 3.2 % on amlodipine monotherapy and 4.2–5.0 % on valsartan monotherapy). Dizziness was the second most common adverse event, reported in 1.4–2.9 % of patients on combination therapy and 1.0–2.0 % on monotherapy.
5 Focus on Combination Amlodipine/Valsartan in Non-whites With Hypertension
Results of several studies suggest that some RAASblocking drugs manifest diminished average BP responses in black patients relative to other drug classes (i.e., calcium channel blockers, thiazide diuretics). However, the use of multiple antihypertensive agents has been shown to offset any racial/ethnic differences in response to therapy. Moreover, RAAS pharmacological blockade provides greater cardiorenal protection than other non-RAAS drug classes. A major renoprotective effect is demonstrated with ramipril in African Americans with hypertensive nephropathy, a group at risk for more rapid loss of kidney function over time. Hispanics/Latinos and Asians with hypertension are also likely to benefit from the use of RAAS inhibitors, especially given that these patients pose a challenge to BP control secondary to their high prevalence of other cardiovascular risk factors such as obesity, diabetes, and metabolic syndrome. Thus, there is a good rationale for the use of RAAS inhibitors as foundation therapy in these high-risk patients, with diuretic or calcium channel blocker added as needed.
Dihydropyridine calcium channel blockers and angiotensin receptor blockers have complementary mechanisms of action (Fig. 1), and each of these drug classes is recommended in the prevention and/or treatment of most complications of hypertension (Fig. 2). The following sections and Table 1 summarize the results of studies with combination amlodipine/valsartan in non-white populations with hypertension, with a focus on blacks, Hispanics/Latinos, and Asians. Since these drugs are widely utilized in the USA in hypertension pharmacotherapy, these particular agents, representing the dihydropyridine calcium channel blocker and angiotensin receptor blocker drug classes, will be the main focus of discussion. Both valsartan and amlodipine have been extensively studied, with a wealth of BP and outcomes data.
(Enlarge Image)
Figure 1.
Complementary mechanisms of action (MOA) of dihydropyridine calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) in lowering blood pressure (BP). Reprinted from Neutel [47], with permission from JTE Multimedia
(Enlarge Image)
Figure 2.
Conditions favoring the use of dihydropyridine calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) according to guidelines for the management of hypertension. Reprinted with permission of Dove Medical Press Ltd, from Waeber and Ruilope [48]; permission conveyed through Copyright Clearance Center, Inc
A search of PubMed was conducted through to 25 February 2013, using the title/abstract key words (amlodipine AND valsartan AND [hypertension OR hypertensive] AND [black(s) OR African American(s) OR Hispanic(s) OR Latino(s) OR Mexican(s) OR Asian(s)]). This search revealed a total of 19 articles in the English language. A review of the abstracts from this search and/or safety evaluation of combination amlodipine/valsartan in the non-white populations of interest [42, 53–58]. The authors were aware of and included an additional study that was not identified in the PubMed search. In total, these studies comprised 1,111 black, 389 Hispanic/Latino, and 3,094 Asian patients with hypertension.
5.1 Sub-Saharan African Blacks
Even though hypertension hardly existed in black Africa in the first half of the 20th century, more recently, in those aged 65 years and over, hypertension has been shown to affect 30–60 % of African blacks. Moreover, this proportion is steadily approaching the 60–70 % range in the USA for blacks of similar age. Thus, reducing BP and controlling hypertension are critical factors in preventing CVD.
In the Newer versus Older Antihypertensive agents in African Hypertensive patients (NOAAH) trial, Odili and colleagues compared the BP-lowering efficacy of a combination of newer (without a diuretic) versus older (with a diuretic) antihypertensive agents in black patients with hypertension born and living in sub-Saharan Africa. The NOAAH study compared two SPCs for control of BP in African patients 30–69 years of age (mean age 51 years) with stage 1 or 2 hypertension (systolic/diastolic BP: 140–179/90–109 mmHg) and no more than two additional risk factors. After a 4-week wash-out period, 140 patients were randomized to once-daily bisoprolol/hydrochlorothiazide (HCTZ) 5/6.25 mg or amlodipine/valsartan 5/160 mg, with permitted up-titration of the bisoprolol and amlodipine doses to 10 mg to achieve BP<140/90 mmHg. At randomization, the bisoprolol/HCTZ and amlodipine/valsartan groups were similar with respect to demographic characteristics, and the overall combined systolic/diastolic BP was 153.9/91.5 mmHg. After randomization, in both groups combined, BP dropped by 18.2/10.1 mmHg at week 2 (n = 122), 19.4/11.2 mmHg at week 4 (n = 109), 22.4/12.2 mmHg at week 8 (n = 57), and 25.8/15.2 mmHg at week 12 (n = 49). The BP control rate of <140/90 mmHg was [65 % by week 2. Thus, NOAAH confirmed that SPC therapy can achieve BP control quickly in black patients born and living in sub-Saharan Africa and that randomized clinical trials of antihypertensive drugs in this indigenous population are feasible.
Although most studies have been done in blacks of African descent in the USA, there are data suggesting that an increase in the incidence of hypertension in blacks living in sub-Saharan Africa is leading to an increase in heart failure and CVD. In a recent (2012) study by Damasceno and colleagues, a prospective, multicenter, observational survey collected data on patients with acute heart failure (AHF) who had been admitted to 12 university hospitals in nine African countries (Sub-Saharan Africa Survey of Heart Failure [THESUS-HF]). The THESUS-HF survey enrolled 1,006 patients presenting with AHF between 2007 and 2010; mean age was 52.3 years, 50.8 % were women, the predominant race was black African (98.5 %), and mean left ventricular ejection fraction was 39.5 %. The most common reason for heart failure was noted to be hypertension (45.4 %), while rheumatic heart disease (14.3 %) and ischemic heart disease (7.7 %) were not as commonly documented causes of AHF. The median hospital stay was 7 days, with an in-hospital mortality of 4.2 % and an estimated 180-day mortality of 17.8 % (95 % confidence interval 15.4–20.6). Overall, the THESUS-HF survey demonstrated that in African patients, AHF is primarily due to a non-ischemic cause, most commonly hypertension; occurs equally among genders, usually in middle-aged adults; and is associated with high mortality.
5.2 African Americans
The EXforge evaluation in Stage Two hypertensives of AfricaN Descent (EX-STAND) study was a 12-week, multicenter, double-blind, prospective, parallel-group trial of 572 black patients (mean age 53 years) with stage 2 hypertension (mean sitting systolic blood pressure [MSSBP] 160–199 mmHg) in the USA. Patients were randomized to either combination amlodipine/valsartan 5/160 mg or amlodipine 5-mg monotherapy. At 2 weeks, doses were force-titrated to 10/160 mg and 10 mg, respectively. At 4 weeks, there was optional up-titration to 10/320 mg in the combination-therapy arm if MSSBP was C130 mmHg. The combination of amlodipine/valsartan attained greater and faster reductions in BP: by week 8, combination amlodipine/valsartan significantly lowered MSSBP more than monotherapy (33.3 vs. 26.6 mmHg; P< 0.0001). A BP goal of<140/90 mmHg was achieved by 49.8 and 30.2 % of patients, respectively (P< 0.0001).
A subgroup analysis of two 8-week, multicenter, randomized, double-blind, placebo-controlled studies (n = 3,161) included 2,508 white patients (mean age 56 years) and 201 black patients (mean age 50 years) with stage 1 or 2 hypertension (mean sitting diastolic blood pressure [MSDBP] 95–109 mmHg). Patients received amlodipine monotherapy, valsartan monotherapy, or a combination of these agents at various dosages ( Table 1 ). Combination therapy was significantly more effective in lowering BP than treatment with the respective monotherapies. In blacks, the greatest reduction in MSDBP was seen with amlodipine/valsartan 5/320 mg (17.9 mmHg), which was consistent with the reduction seen in whites (15.5 mmHg).
In a post hoc analysis of patients with hypertension enrolled in a 12-week, multicenter, randomized, double-blind clinical trial (EXforge TaRget Achievement [EXTRA]), treatment responses with combination amlodipine/valsartan 10/320 mg versus amlodipine/valsartan 5/160 mg were evaluated among a diverse cohort (474 white, 198 black, and 165 Hispanic individuals ranging in age from a mean of 51–57 years). Patients were treatment naïve or nonresponders (MSSBP 150–199 mmHg) to angiotensin receptor blocker monotherapy (other than valsartan). Regardless of race or ethnic background, results demonstrated that more intensive dosage treatment provided greater BP lowering versus moderate treatment. In blacks, moderate treatment for 4 weeks (before addition of HCTZ) lowered MSSBP by 18.1 mmHg and allowed 26.9 % of patients to achieve BP goal (<140/90 mmHg), whereas intensive treatment lowered MSSBP by 20.4 mmHg with 37.1 %of patients attaining BP goal (P = not significant/P< 0.01). Further improvement in BP was seen with the addition of HCTZ.
Across all studies, the combination of amlodipine/valsartan was well tolerated ( Table 1 ). Peripheral edema was reported at an incidence ranging from 2.1 to 12.6 % in the black population, which was within the range reported in control patients (9.5–15.4 %). Other adverse events reported among blacks treated with amlodipine/valsartan included headache (3.2–6.1 vs. 5.3–7.7 % in controls) and dizziness (2.1–6.7 vs. 2.5 % in controls).
5.3 Hispanics/Latinos
In the EXforge EFFicacy and Control in Treatment of Stage 2 hypertension (EX-EFFeCTS) study, the efficacy and safety of combination amlodipine/valsartan versus amlodipine alone were compared in 646 patients (mean age 58 years) with stage 2 hypertension (MSSBP 160–199 mmHg). In this 8-week, multicenter, randomized, double-blind study, approximately one third of the study population (n = 224; 34.7 %) was of Hispanic/Latino ethnicity. The initiating doses were amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks, with force-titration to amlodipine/valsartan 10/160 mg or amlodipine 10 mg, respectively, for an additional 6 weeks. At 4 weeks (primary endpoint), MSSBP demonstrated an improvement in Hispanic/Latino patients receiving amlodipine/valsartan compared with those receiving amlodipine alone (-29.1 vs. -23.0 mmHg; P< 0.05). An MSSBP<140 mmHg was achieved by 55.1 and 35.8 % of Hispanic/Latino patients, respectively (P value not reported).
The previously mentioned post hoc analysis by Ofili and colleagues included 165 (22.7 %) Hispanic patients. In this population, treatment with combination amlodipine/valsartan for 4 weeks lowered MSSBP by 17.5 mmHg (moderate treatment) or 23.4 mmHg (intensive treatment) (P< 0.01). Corresponding BP control rates were 33.3 and 54.8 % (P< 0.01). As in black people, the addition of HCTZ provided further antihypertensive efficacy.
In both of the above studies, efficacy results in Hispanic/Latino patients were similar to those seen for other race groups and the overall population ( Table 1 ). In addition, the combination of amlodipine/valsartan was well tolerated, providing support for use of this regimen in Hispanic/Latino patients. The most commonly reported adverse event was peripheral edema: 8.2 % with the intensive regimen and 2.5 % with the moderate regimen in one study and 12.8 % with combination therapy versus 17.6 % with amlodipine monotherapy in the other study. Across both studies, headache was reported by 2.4–4.9 % of patients receiving amlodipine/valsartan and 3.1 % of patients receiving amlodipine alone.
5.4 Asians
Due to less-robust data in Asian Americans, clinical data are discussed for non-American Asian cohorts. Recently, an open-label, observational, non-interventional, surveillance study was designed to evaluate the safety and effectiveness of the amlodipine/valsartan combination. There were 2,729 participants with systolic BP [140 mmHg and/or diastolic BP[90 mmHg from 298 centers around the world, including China, Malaysia, Pakistan, Bangladesh, Egypt, and Russia. The cohort was composed of 54.5 % men, 54.2 % Asian, and 44.6 % white. Mean age was 57.9 years, baseline BP was 163.1/96.2 mmHg, and 86.5 % had prior hypertension therapy that was discontinued. During the 12 weeks of treatment with amlodipine/valsartan, there was a significant systolic/diastolic BP reduction of 33.2/16.9 mmHg (P< 0.0001), resulting in a substantially lower final BP reading of 129.9/79.3 mmHg. Additionally, Chazova and colleagues demonstrated a dose-dependent effect with amlodipine/valsartan where the smallest BP reduction was 29.2/15.1 mmHg with the 5/80- mg dose (P< 0.0001) and the greatest BP reduction was 43.6/22.4 mmHg with the 10/160-mg dose (P< 0.0001). BP lowering was linked to the severity of baseline BP levels.
In an 8-week, multicenter, randomized, double-blind trial, Ke and colleagues studied the effects of the SPC of amlodipine/valsartan compared with amlodipine alone in an Asian hypertensive population that was non-responsive (MSDBP 90–109 mmHg) to amlodipine 5-mg monotherapy. Baseline characteristics were similar between treatment groups: the majority of patients were male (65.1 %) and Chinese (86.4 %); mean age was 53.8 years; and mean seated systolic/diastolic BP was 139.5/94.5 mmHg. After a 1–4-week washout period, a total of 698 patients were randomized to either amlodipine/valsartan 5/80 mg or amlodipine 5 mg. Results showed that the reduction in systolic/diastolic BP at the week 8 endpoint was significantly greater with amlodipine/valsartan than with amlodipine (11.4/9.7 vs. 7.4/7.1 mmHg; P< 0.0001), with a correspondingly higher BP-control rate (<140/90 mmHg): 69.2 versus 57.6 %; P = 0.0013.
Huang and colleagues evaluated the efficacy of the SPC of amlodipine/valsartan in another 8-week, randomized, double-blind study of 918 Asian patients (mean age 52 years) with stage 1 or 2 hypertension (MSDBP 90–109 mmHg) from 30 centers inAsiawhowere not responding to valsartan 80-mg monotherapy. The patients were randomized to receive amlodipine/valsartan 5/80 mg (n = 308), valsartan 80 mg (n = 307), or valsartan 160 mg (n = 303).Results at theweek 8 endpoint revealed reductions in BP of 12.5/10.8 mmHg for amlodipine/valsartan 5/80 mg, which were significantly greater than those for valsartan 80 mg (6.0/6.3 mmHg) or valsartan 160 mg (7.7/7.2 mmHg) (P< 0.0001). Regardless of baseline BP, at theweek 8 endpoint, a significant proportion of patients achieved BP control with amlodipine/valsartan 5/80 mgcompared with the valsartanmonotherapies (Table 1; P< 0.01 for both comparisons).
As shown in Table 1, the combination of amlodipine/valsartan was well tolerated across each of the above studies. Across the three studies identified in the Asian population assessments, the most commonly reported adverse event was hyperlipidemia (up to 4.3 % of patients on amlodipine/valsartan vs. 3.2 % on amlodipine monotherapy and 4.2–5.0 % on valsartan monotherapy). Dizziness was the second most common adverse event, reported in 1.4–2.9 % of patients on combination therapy and 1.0–2.0 % on monotherapy.