Outcome Trials in the Therapeutic Management of Hypertension in East Asians

Abstract

According to the most recent epidemiological data, the prevalence of hypertension ranged from about 25% in Chinese living either in the mainland or in Taiwan and Koreans, to approximately 40% in Mongolians. The control rate of hypertension was about 35% in Koreans and Japanese, 24% in Mongolians, and less than 10% in Chinese. Four placebo-controlled trials in China unequivocally proved that antihypertensive therapy may prevent stroke and other cardiovascular complications in hypertension or patients with a history of stroke or transient ischemic attack. Four actively-controlled trials in Japan did not show significant difference between various classes or combinations of antihypertensive drugs. Two trials that compared intensive with less intensive blood pressure control in elderly Japanese hypertensive patients did not show further benefit of controlling systolic blood pressure to a level below 140 mmHg in comparison with blood pressure control to a level of 140 mmHg or above. These trials that compared various classes of antihypertensive drugs or intensive with less intensive blood pressure control often had small sample size and hence inadequate power to detect modest or moderate benefit. There is still a need for high quality outcome trial data in East Asians.

Main article text

Introduction

After World War II, the prevalence of hypertension in East Asians increased substantially in most countries and regions. Taking China as an example, the prevalence of hypertension increased from less than 10% before 1980 [1, 2] to approximately 25% in the latest nationwide survey in 2012 [3, 4]. This increase can to some extent be attributable to the increased number of elderly people over the years. However, Westernized lifestyle characterized by high salt, high fat, high sugar and high calorie diet and physical inactivity could be a major risk factor for the increasing prevalence of hypertension in these populations. If the most recent data in East Asians is compared across countries or regions, the prevalence of hypertension ranged from about 25% in Chinese living either in the mainland [4] or in Taiwan [5] and Koreans [6], to approximately 40% in Mongolians [7] (Table 1). The overall prevalence of hypertension was not reported in the most recent Japanese national blood pressure survey in 2010. The age-specific data suggested that the prevalence of hypertension in Japanese was high [8]. The prevalence of hypertension in persons of 60–69 years was more than 60% in both men and women [8], much higher than the 49.1% prevalence in Chinese of 60 years or older in 2002 [4].

Table 1

Characteristics of Epidemiologic Studies on Hypertension in East Asians.

Country or region and year [Reference]	Age range, years	Number of subjects	Prevalence, %	Awareness, %	Treatment, %	Aware and treated, %	Control, %	Treated and controlled, %
China							]
1991 [3]	≥15	950,356	11.3	26.6	12.1	45.5	2.8	23.1
2002 [4]	≥18	141,892	18.8	30.2	24.7	81.8	6.1	25.0
2002 [4]	≥60	NR	49.1	37.6	36.2	96.3	7.6	24.1
Japan [8]
2010	30–39	NR	Men 20, Women 5.6	–	–	–	–	–
2010	40–49	NR	Men 29.9, Women 12.6	–	–	–	–	–
2010	50–59	NR	Men 63.2, Women 38.4	–	Men 43.4, Women 31.2	–	Men 32.1, Women 44.1	–
2010	60–69	NR	Men 65.6, Women 62.3	–	Men 50.6, Women 68.8	–	Men 29.9, Women 40.9	–
2010	70–79	NR	Men 80.8, Women 71.2	–	Men 29.9, Women 12.6	–	Men 33.3, Women 40.5	–
Korea [6]
2008	≥30	9146	24.9	60.6	52.2	86.2	36.7	70.3
Mongolia [7]
2009	15–64	4502	36.5	65.8	35.9	54.6	24.1	67.1
Taiwan [5]
1993–1996	≥19	6479	23.5	–	–	–	–	–

NR, not reported.

There is not much high quality data on the management of hypertension except for the national blood pressure surveys in China [4] and Korea [6]. According to the currently available data, Koreans [6] and Japanese [8] seemed to have higher awareness, treatment and control rates of hypertension than other East Asian populations [4, 5, 7] (Table 1). The control rate of hypertension was about 35% in Koreans [6] and Japanese [8], 24% in Mongolians [7], and less than 10% in Chinese [4]. Nevertheless, several classes of efficacious antihypertensive drugs are readily available for the management of hypertension in most countries or regions. In the past several decades, several outcome trials on the therapeutic management of hypertension were conducted in East Asians. This review article summarizes the literature of outcome trials on hypertension in this region.

Placebo-Controlled Trials

Since the late 1980s, several placebo-controlled outcome trials were conducted in China to investigate whether antihypertensive therapy would prevent cardiovascular complications in hypertensive patients (Table 2) [9–12].

The Systolic Hypertension in China (Syst-China) trial investigated whether active antihypertensive treatment would prevent fatal and non-fatal stroke in 2394 elderly (≥60 years) patients with isolated systolic hypertension (systolic blood pressure ≥160 mmHg and diastolic blood pressure <95 mmHg). Active antihypertensive treatment was initiated by nitrendipine, with the possible addition of captopril and hydrochlorothiazide, to achieve the goal systolic blood pressure of 150 mmHg or lower. At 2 years of follow-up, active treatment (n=1253), compared with placebo (n=1141), reduced systolic/diastolic blood pressure by 9.1/3.2 mmHg. During a median follow-up of 3 years, active treatment reduced the incidence rate of fatal and non-fatal stroke by 38%. Active treatment also significantly reduced all-cause mortality, cardiovascular mortality, stroke mortality, and all fatal and non-fatal cardiovascular endpoints by 39%, 39%, 58%, and 37%, respectively [9].

The Shanghai Trial of Nifedipine in the Elderly (STONE) was a single-blind study in 1632 elderly (60–79 years) patients with hypertension (systolic blood pressure 160–219 mmHg or diastolic blood pressure 96–124 mmHg), alternately allocated to either nifedipine (n=817) or placebo (n=815). During a mean follow-up of 30 months, nifedipine treatment reduced systolic/diastolic blood pressure by 9.3/5.5 mmHg, and the incidence of fatal and non-fatal stroke by 58%. Nifedipine also significantly reduced the incidence of all fatal and non-fatal cardiovascular events by 60% [10].

The Felodipine Event Reduction (FEVER) trial compared felodipine (5 mg daily) with placebo in 9800 patients (50–79 years of age) with a systolic/diastolic blood pressure in the range of 140–180/90–100 mmHg after 6 weeks of treatment with hydrochlorothiazide 12.5 mg per day. During a mean follow-up of 3.3 years, felodipine, compared with placebo reduced systolic/diastolic blood pressure by 4.2/2.1 mmHg, and the primary endpoint (fatal and non-fatal stroke) by 27%. Felodipine also significantly reduced all cardiovascular events, all cardiac events, all-cause mortality, coronary events, heart failure, cardiovascular death, and cancer by 27%, 35%, 31%, 32%, 30%, 33%, and 36%, respectively [11].

The Post-stroke Antihypertensive Treatment Study (PATS) was a double-blind blood pressure lowering trial with indapamide (2.5 mg daily) in hypertensive and non-hypertensive patients with a history of stroke or transient ischemic attack. During a median follow-up of 2 years, indapamide reduced systolic/diastolic blood pressure by 5/2 mmHg, and the incidence of recurrent stroke by 29%. Indapamide also significantly reduced the incidence of all fatal and non-fatal cardiovascular endpoints by 23% [12].

Actively-Controlled Trials

Since the 1990s, several actively-controlled outcome trials were conducted in Japan to compare various classes or combinations of antihypertensive drugs as initial therapy for the prevention of cardiovascular complications (Table 2) [13–16]. All these trials had an open design, except for the double-dummy National Intervention Cooperative Study in Elderly Hypertensives (NICS-EH) [13], and had a relatively small sample size in the detection of a modest or moderate difference between antihypertensive drug classes.

Table 2

Characteristics of Trials.

Trial	Masking	Number of patients	Antihypertensive treatment (mg)	Age, years		SBP/DBP, mmHg			FU time	Favorable results
				Entry criteria	Mean (SD)	Entry criteria	Mean (SD) at baseline	Difference during FU
Active treatment vs. placebo or no treatment
FEVER [11]	Double	9800	HCTZ (12.5)+felodipine (5–10) vs. HCTZ (12.5)+placebo	50–79	61.5 (7.2)	140–180/90–100 on HCTZ (12.5 mg)	154.3/91.2 (17.5/9.6)	4.2/2.1	40 months	Felodipine
PATS [12]	Double	5665	Indapamide (2.5) vs. placebo	None	60 (8)	None	154/93 (23/13)	5/2	2 years	Indapamide
STONE [10]	Single	1632	Nifedipine vs. placebo	60–79			168.5/97.7	9.4/5.5	30 months	Nifedipine
Syst-China [9]	Double	2394	Nitrendipine (10–40)+captopril (12.5–50)+HCTZ (12.5–50) vs. placebo	≥60	66.5 (5.5)	160–219/<95	170.5/86.0 (11.1/6.8)	9.1/3.2	3.0 years	Active treatment
Actively-controlled trials
CASE-J [15]	Open	4728	Amlodipine (2.5–10) vs. Candesartan (4–8)	None	63.8 (10.5)	140–179/90–109 (<70 years) or 160–179/90–109 (≥70 years)	162.8/91.7 (14.2/11.2)	1.7/0.6	3.2 years	Neutral
COPE [16]	Open	3293 (3501)*	Benidipine (4)+ARB vs. Benidipine (4)+a-blocker vs. Benidipine (4)+diuretic	40–85	63.1 (10.7)	140–199/90–119 on/off treatment	153.9/88.8 (11.6/9.7)	0.8/0.6	3.61 years	Neutral
JMIC-B [14]	Open	1650	Nifedipine Retard (20–40) vs. ACE inhibitors	<75	64.5 (8.5)	≥150/90–120 or treated	146/82 (19.5/11.5)	4/1	36 months	Neutral
NICS-EH [13]	Double	414	Nicardipine SR (40–80) vs. Trichlormethiazide (2–4)	≥60	69.8 (6.5)	160–220/<115	172.3/93.8 (11.9/10.2)	−1/−1	3 years	Neutral
Intensive vs. less intensive
JATOS [20]	Open	4418 (4508)*	<140 vs. 140–159 mmHg	65–85	73.6 (5.3)	≥160/	171.6/89.1 (9.8/9.5)	9.7/3.3	2 years	Neutral
VALISH [21]	Open	3260	<140 vs. 140–149 mmHg	70–84	76.1 (4.1)	160–199/−	169.5/81.5	5.4/1.7	3.07 years	Neutral
Subgroup of multinational trials
HYVET [24]	Double	3845 (1526)†	Indapamide (1.5)+perindopril (2–4) vs. placebo	≥80	83.6 (3.2)	160–199/<110	173.0/90.8 (8.5/8.5)	15.0/6.1	1.8 years	Active treatment
PROGRESS [22]	Double	6105 (2352)†	Perindopril (4)+indapamide (2.5) vs. placebo	None	64 (10)	<180/<110	147/86 (19/11)	9/4	3.9 years	Active treatment
HOPE-3 [26]	Double	12,705 (3691)	Candesartan (16)+HCTZ (12.5)	≥55 (men) ≥65 (women)	65.7 (6.4)	None	138.1/81.9 (14.8/9.3)	6/3 (2.2/1.1 in Chinese patients)	5.6 years	Neutral

FU, follow-up; HCTZ, hydrochlorothiazide; SBP/DBP, systolic/diastolic blood pressure; SR, sustained release. Acronyms of trials are explained in a separate section of this article.

^*The number of patients analyzed was reported together with the number of randomized patients in the parentheses.

^†In the parentheses are the number of patients recruited in China for the HYVET [24, 25] and HOPE-3 [26] trials and in China and Japan for the PROGRESS trial [22, 23].

NICS-EH compared two outdated antihypertensive drugs (sustained-release nicardipine [n=204] versus trichlormethiazide [n=210]) in 414 elderly (≥60 years) patients with hypertension (systolic blood pressure 160–220 mmHg and diastolic blood pressure <115 mmHg). During 5 years of follow-up, nicardipine was slightly less efficacious than trichlormethiazide in lowering systolic/diastolic blood pressure (−1/−1 mmHg). During follow-up, a total of 39 events occurred in the two groups combined, and no significant difference was observed in any outcome between the two treatment groups [13].

The Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) trial compared nifedipine retard with angiotensin-converting enzyme (ACE) inhibitors (enalapril 5–10 mg, imidapril 5–10 mg, or lisinopril 10–20 mg, once daily) in 1650 patients with both hypertension and coronary heart disease, diagnosed according to coronary angiography (stenosis ≥75%), a history of angina pectoris (>2 episodes per week), or ST-segment depression of at least 1 mm during the treadmill exercise test. During a mean follow-up of 36 months, blood pressure reductions were greater in the nifedipine group than the ACE inhibitors group (−4/−1 mmHg). The incidence rate of the primary endpoint (cardiac events: cardiac death or sudden death, myocardial infarction, hospitalization for angina pectoris or heart failure, serious arrhythmia, and coronary interventions) was similar in the nifedipine (116 events, 14.0%) and ACE inhibitors (106 events, 12.9%) groups (+5%; P=0.75) [14].

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial compared amlodipine- with candesartan-based antihypertensive regimens in 4728 high risk hypertensive patients. To achieve the goal blood pressure of 140/90 mmHg or below, diuretics, a-blockers, b-blockers, and/or ab-blockers could be added. During a mean follow-up of 3.2 years, systolic/diastolic blood pressures were 1.7/0.6 mmHg lower in the amlodipine group than the candesartan group, even though more patients in the candesartan group required addition of other antihypertensive drugs (54.5% vs. 42.7%; P<0.0001). The incidence rates of the primary (sudden death and cerebrovascular, cardiac, renal, and vascular events) and secondary endpoints were not statistically different between the two treatment groups. The risk of stroke was slightly but non-significantly lower in the amlodipine group than the candesartan group (−23%; P=0.28) [15].

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was designed to compare three combinations of antihypertensive drugs in the prevention of cardiovascular events in 3501 patients of 40–85 years old and with uncontrolled hypertension (systolic/diastolic blood pressure ≥140/90 mmHg) by the calcium channel blocker benidipine 4 mg/day. Patients were randomly assigned to receive angiotensin receptor blocker (n=1167), β-blocker (n=1166), or thiazide diuretic (n=1168) in addition to benidipine. During a median follow-up of 3.61 years, blood pressure was reduced similarly in the three groups, with a control rate of 64.1%, 66.9%, and 66.0% at the end of treatment in the benidipine–angiotensin receptor blocker, benidipine–β-blocker, and benidipine–thiazide groups, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively, with a hazard ratio of 1.26 (P=0.35) in the benidipine–angiotensin receptor blocker and 1.54 (P=0.06) in the benidipine–β-blocker groups compared with the benidipine–thiazide group [16].

None of these trials had sufficient power to detect a modest or moderate but clinically relevant difference between various classes of antihypertensive drugs. However, if the results of these trials were pooled with that of studies in other populations, there could be significant difference between different drug classes. For instance, if the CASE-J trial [15] was combined with the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) [17] and Irbesartan Diabetic Nephropathy Trial (IDNT) [18] trials that also compared amlodipine with an angiotensin receptor blocker, amlodipine provided superior protection against stroke and myocardial infarction by 16% and 17%, respectively [19].

Intensive Versus Less Intensive Blood Pressure Control

Two Japanese trials compared intensive with less intensive blood pressure control in elderly hypertensive patients [20, 21]. These two trials again had a relatively small sample size and hence inadequate power in the detection of a modest or moderate difference between different levels of blood pressure control.

The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) compared the 2-year effect of intensive (systolic blood pressure <140 mmHg, n=2212) versus less intensive treatment (systolic blood pressure 140–159 mmHg, n=2206) in 4418 elderly (65–85 years) patients with essential hypertension (pretreatment systolic blood pressure ≥160 mmHg). The first line drug was a long-acting calcium channel blocker, efonidipine. At last clinic visit, systolic/diastolic blood pressures were significantly lower in the intensive than the less intensive treatment group (135.9/74.8 vs. 145.6/78.1 mmHg), with a between group difference of 9.7/3.3 mmHg. However, no significant difference between the two treatment groups was observed for the incidence of the primary endpoint (combination of cardiovascular disease and renal failure, 86 patients in each group; P=0.99) and for total mortality (54 in the intensive-treatment group vs. 42 in the less intensive-treatment group, P=0.22). In a post-hoc analysis, however, there was interaction between age and treatment for the primary endpoint (P=0.03). Intensive blood pressure control tended to confer benefit in younger elderly (65–74 years) but harm in older elderly (≥75 years) [20].

The Valsartan in Elderly Isolated Systolic Hypertension (VALISH) Study compared intensive (systolic blood pressure ≤140 mmHg, n=1545) with less intensive blood pressure control (systolic blood pressure 140–150 mmHg, n=1534) in the prevention of cardiovascular mortality and morbidity in 3260 elderly (70–84 years) patients with isolated systolic hypertension (systolic blood pressure 160–199 mmHg). At baseline, age averaged 76.1 years, and systolic/diastolic blood pressures were 169.5/81.5 mmHg. At 3 years of follow-up, systolic/diastolic blood pressures were 136.6/74.8 mmHg and 142.0/76.5 mmHg, respectively, with a between-group difference of 5.4/1.7 mmHg. During a median follow-up of 3.07 years, the overall rate of the primary composite endpoint was slightly lower in the intensive (10.6/1000 patient-years) than the less intensive blood pressure control group (12.0/1000 patient-years, hazard ratio 0.89; 95% CI 0.60–1.34; P=0.38). However, none of the differences between the two groups reached statistical significance for any outcome [21].

Subgroups of Multinational Trials

Since the 1990s, several multinational trials in blood pressure lowering treatment involved East Asians, such as the perindopril PROtection aGainst REcurrent Stroke Study (PROGRESS) [22, 23], the HYpertension in the Very Elderly Trial (HYVET) [24, 25], and the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial [26].

The PROGRESS trial was designed to determine the effects of a blood-pressure lowering regimen in 6105 hypertensive and non-hypertensive patients with a history of stroke or transient ischemic attack, recruited from 172 centers in Asia, Australasia, and Europe. Over 4 years of follow-up, active treatment (perindopril 4 mg daily with the possible addition of indapamide, n=3051), compared with placebo (n=3054), reduced blood pressure by 9/4 mmHg, and the incidence of fatal and non-fatal stroke by 28%. Active treatment also significantly reduced the risk of total major vascular events by 26% [22]. Of particular note, the PROGRESS trial included 2335 Asians, either Chinese or Japanese. Active treatment reduced systolic/diastolic blood pressure by 10.3/4.6 mmHg in Asians and by 8.1/3.6 mmHg in Western participants. The risk reduction tended to be greater in Asians for stroke (39% vs. 22%, P for homogeneity=0.10) and major vascular events (38% vs. 20%, P for homogeneity=0.06) [23].

The HYVET trial investigated whether antihypertensive treatment would reduce the risk of stroke in 3845 very elderly (≥80 years) patients with hypertension (systolic blood pressure ≥160 mmHg and diastolic blood pressure <110 mmHg), recruited from Australasia, China, Europe, and Tunisia. Active treatment was started by indapamide (sustained release, 1.5 mg) with the possible addition of perindopril 2 or 4 mg. At 2 years of follow-up, active treatment (n=1933), compared with placebo (n=1912), reduced systolic/diastolic blood pressure by 15.0/6.1 mmHg. During a median follow-up of 1.8 years, active treatment reduced the incidence of fatal and non-fatal stroke by 30%, stroke mortality by 39%, all-cause mortality by 21%, cardiovascular mortality by 23%, and heart failure by 64% [24]. The HYVET trial included 1526 patients from China. Although the outcome results in Chinese were not published separately, the overall results should apply for Chinese people of 80 years or older [25].

The recently published HOPE-3 trial was a 2×2 factorial study for blood pressure and lipid-lowering treatments in 12,705 patients at intermediate cardiovascular risk. There was no threshold of blood pressure for inclusion into the trial. Mean systolic/diastolic blood pressures at baseline were 138.1/81.9 mmHg. Over a median follow-up of 5.6 years, active antihypertensive treatment with a single-pill combination of candesartan 16 mg/hydrochlorothiazide 12.5 mg per day, compared with placebo, reduced systolic/diastolic blood pressures by 6/3 mmHg, but did not influence either the risk of the two co-primary endpoints (cardiovascular mortality, stroke, and myocardial infarction without [definition 1] or with [definition 2] cardiac arrest, congestive heart failure and revascularization) or the risk of any secondary endpoint. Nonetheless, a post-hoc analysis suggested that active antihypertensive treatment significantly reduced the risk of both co-primary outcomes 1 and 2 by 27% and 24%, respectively, in the top tertile of baseline systolic blood pressure. The mean systolic/diastolic blood pressure reductions were only 2.2/1.1 mmHg in 3691 patients recruited from China, much smaller than in patients recruited from other regions. However, the outcome results were not different between the Chinese and patients from other regions (P=0.48 for homogeneity across regions) [26].

Conclusions and Future Perspectives

There is some but insufficient outcome trial data from East Asians. Nonetheless, the currently available data suggested that antihypertensive treatment was highly efficacious in the prevention of cardiovascular complications especially stroke. The trials that compared intensive with less intensive antihypertensive therapy did not prove superiority of intensive blood pressure lowering to a level below 140 mmHg in elderly Japanese. These trials had a relatively small sample size and short duration of follow-up, and therefore probably had inadequate power for the detection of modest or moderate benefit. There is a need for high quality outcome trials in East Asians, especially in the context of the recent Systolic Blood Pressure Intervention Trial (SPRINT) that clearly demonstrated outcome benefit of intensive systolic blood pressure control to a level of 120 mmHg [27].

Conflict of Interest

Dr. Wang reports receiving lecture and consulting fees from MSD, Novartis, Pfizer, Sankyo, Sanofi, and Servier. Dr. Li. declares no conflict of interest.

Acronyms of Trials

CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan Trial) [15]; COPE (The Combination Therapy of Hypertension to Prevent Cardiovascular Events) [16]; FEVER (Felodipine Event Reduction Study) [11]; HOPE-3 (Heart Outcomes Prevention Evaluation-3) [26]; HYVET (Hypertension in the Very Elderly Trial) [24, 25]; IDNT (Irbesartan Diabetic Nephropathy Trial) [18]; JATOS (The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients) [20]; JMIC-B (Japan Multicenter Investigation for Cardiovascular Diseases-B) [14]; NICS-EH (National Intervention Cooperative Study in Elderly Hypertensives) [13]; PATS (Post-stroke Antihypertensive Treatment Study) [12]; PROGRESS (Perindopril PrOtection Against Recurrent Stroke Study) [22, 23]; SPRINT (Systolic Blood Pressure Intervention Trial) [27]; STONE (Shanghai Trial of Nifedipine in the Elderly) [10]; Syst-China (Systolic Hypertension in China trial) [9]; VALISH (The Valsartan in Elderly Isolated Systolic Hypertension) [21] and VALUE (Valsartan Antihypertensive Long-term Use Evaluation (VALUE) [17].

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