159

Symposium

Control of Blood Pressure and Prevention of End-Organ Damage in Patients with Accelerated

Hypertension by Combination with Arotinolol

and Extended Release Nifedipine

Hiromichi SUZUKI, Hidetomo NAKAMOTO, Hironori NEMOTO, Souichi SUGAHARA,

and Hirokazu OKADA

In patients with accelerated (malignant) hypertension, end-organ damage is the determinant factor for

prognosis. Although recent advances in antihypertensive therapy have improved the outcome of patients with accelerated hypertension, the effectiveness of antihypertensive therapy still remains less convinced.

In this study, we followed 13 patients clinically diagnosed with accelerated hypertension (defined as di-

astolic blood pressure > 130 mmHg, retinopathy with K-W IV and accelerated renal impairment) for 3 yr. One patient died due to acute myocardial infarction arising from poor compliance with antihypertensive

therapy. One patient was maintained on hemodialysis for 3 yr. One patient was introduced for continuous

ambulatory peritoneal dialysis (CAPD) for a year and then lived without dialysis therapy. The remaining 10

patients were followed for 3 yr. All patients were initially treated with intravenous administration of cal-cium antagonist for reduction of blood pressure, followed by hemodialysis therapy if needed. After stabi-

lization of blood pressure, combination therapy with extended release nifedipine (40 to 80 mg daily) and

arotinolol (20 mg daily) was started. The targets for blood pressure control were a systolic pressure of 135

mmHg and a diastolic pressure of 80 mmHg. If blood pressure control was unsatisfactory, guanabenz (2 to

4 mg before bedtime), a central acting drug, was added. At presentation, the mean diastolic blood pres-

sure (mDBP) among the 10 remaining patients was 134±2 mmHg, the mean serum creatinine (mScr) was

4.5±0.7 mg/dl and the left ventricular mass index (LVMi) as measured by echocardiography was 150±9

g/m2. At 1 yr, the mDBP was reduced to 90±3 mmHg, the mScr to 2.9±0.9 mg/dl and the LVMi to 140± 9

g/m2. At 3 yr, the mDBP was stabilized at 79 ± 3 mmHg, the mScr maintained at 2.2 ± 0.4 mg/dl, and the LVMi reduced to 128 ± 9 g/m2. These results indicate that appropriate blood pressure control is important

for improvement of renal impairment and cardiac damage in patients with accelerated hypertension.

Moreover, combination therapy with arotinolol and extended release nifedipine may be beneficial for this

purpose. (Hypertens Res 2000; 23:159-166)

Key Words: accelerated hypertension, renal failure, left ventricular hypertrophy, calcium antagonist, a j9

blocker

From the Department of Nephrology, Saitama Medical School, Saitama, Japan.

Address for Reprints: Hiromichi Suzuki, M.D., Department of Nephrology, Saitama Medical School, 38 Morohongo, Moroyama-machi,

Iruma-gun, Saitama 350-0495, Japan.

Received October 12,1999; Accepted in revised form November 4, 1999.

160 Hypertens Res Vol. 23, No. 2 (2000)

Introduction

Although the recent development of new antihypertensive agents and the prevalence of antihypertensive therapies are thought to have reduced the incidence of accelerated hypertension and to have improved prognosis, the evi-dence for these improvements remains limited (1, 2). Thus, although several authors have posited that the inci-dence of accelerated hypertension is in decline and the

prognosis improving (3, 4), this is not collaborated by the recent study of Lip et al. (5), who found no decline in the incidence of accelerated hypertension and a relatively

poor prognosis for cases compromised by renal impair-ment. In hypertensive emergencies, intravenous antihyperten-

sive therapy is mandatory, and oral agents can be started after the stabilization of blood pressure. As the choice of oral antihypertensive agents, angiotensin converting en-zyme (ACE) inhibitors are recommended because several human clinical trials have demonstrated that ACE inhibi-tors reduced proteinuria and also prevented progressive renal failure in patients with renal insufficiency from hypertension (6-8). However, in cases of moderate to se-vere renal dysfunction, antihypertensive treatment with ACE inhibitors can actually exacerbate renal dysfunction and hyperkalemia (9). There have been few reports on renal impairment due to accelerated hypertension. At

present, some studies provide evidence of the reno-protective effects of calcium antagonists (10), such as re-tardation of renal growth, reduction of mesangial entrap-ment of macromolecules, and etc. (11).

Cases of accelerated hypertension are often compli-cated by myocardial ischemia, left ventricular hypertro-

phy, and/or renal insufficiency (12-14). For patients with such complications, Nolan and Linas have indicated that intravenous administration of sodium nitroprusside fol-lowed by combination therapy with hydralazine and pro-

pranolol is highly effective (15). Additionally, it is reported that the addition of nifedipine to ~3 receptor blockade, has been provocated to have cardioprotective effects (16, 17). Arotinolol (18, 19), which was developed in Japan, has a structure and action similar to those of carvedilol (20).

In the present study, we performed a three-year follow-up of patients with accelerated hypertension in order to

quantify the efficacy of combination therapy with arotino-lol and extended release nifedipine.

Patients and Methods

Thirteen patients were presented with a symptom of accelerated hypertension to our hospital, over the 3 yr period from 1995 to 1997. We diagnosed these patients as accelerated hypertension by three major symptoms as fol-lows, (1) severe hypertension (diastolic blood pressure

> 130 mmHg), (2) retinal damage (the presence of bilater-al linear or flame-shaped haemorrhages and/or cotton-wool spots) and progressive renal failure (serum creatinine >2.0 mg/dl and/or glomerular filtration rate <50 ml/ min/ 1.73 m3). The diagnosis of any of the underlying causes has greater significance in accelerated hypertension, therefore, secondary causes of hypertension were ex-cluded by endocrinological and radiological examinations, including ultrasonography and computed tomography. Especially, when a renal arterial abnormality or a uni-lateraly diseased kidney was strongly suspected, magnetic resonance image angiography was applied to deny these

possibilities. And when we diagnosed the patient as secondary hypertension from endocrine abnormality or renovascular hypertension, we excluded these patients from our study. Each patient gave their informed written consent to participate in the protocol, which had been approved by our institutional review board.

Blood pressure was controlled by intravenous adminis-tration of nicardipine (2-10 p/kg/min; Yamanouchi Co., Tokyo, Japan). Hemodialysis therapy was utilized for pa-tients experiencing acute renal failure or volume over-load. After blood pressure was well controlled and renal deterioration improved, patients were discharged from our hospital. They were followed-up routinely with visits to the hospital every 2 wk to ensure that they had a good blood pressure control under the medication for 6 mo and after that patients were checked every month for next 30 mo. Antihypertensive treatment was performed using ex-tended release nifedipine at a dose of 40 to 80 mg twice daily and arotinolol 20 mg twice daily. The goal target blood pressure levels were less than 135/80 mmHg. If blood pressure was not sufficiently enough, guanabenz re-duction was added at a dose of 2 to 4 mg at bedtime.

One patient died due to acute myocardial infarction fol-lowing poor compliance with antihypertensive therapy. One patient was maintained on hemodialysis for 3 yr. One patient was introduced for continuous ambulatory

peritoneal dialysis (CAPD) for a year and then lived without dialysis therapy.

Blood Pressure Measurements

During our studies, all the subjects were always examined at the same time (10:00 am-12:00 am) at least 2 h after the patients had ingested their medication. Blood pres-sure was measured in a bed room or an office setting with the conventional cuff method and mercury manometer. Patients were seated for at least 10 min before the measurement. Diastolic blood pressure was determined at Korotokoff phase V.

Suzuki et al: End Organ Damage in Malignant HT 161

Laboratory Measurements

We measured the serum creatinine, serum blood urea ni-

trogen, serum sodium and potassium at admission, during

the hospitalization, and at adequate point during the

follow-up period. Other biochemical examinations were

adequately checked.

Echocardiography

All echocardiography recordings were performed by two experienced investigators using a Hewlett Packard Sonos 1000 system (Hewlett Packard Japan Co., Tokyo, Japan) with a 2.5-MHz transducer according to recommendations of the American Society of Echocardiography (21). M-mode recordings were guided by 2-dimensional views. Left ventricular mass index (LVMI) was calculated according to the formula of Devereux et al. (22). Left ventricular end-diastolic and end-systolic volumes were determined by 2-dimensional echocardiography, and left ventricular ejection (EF) was calculated with standard formulas. Values from at least 3 beats were measured and aver-aged, and intraobserver variability was determined to be 6.8%, 6.2% and 3.8% for end-diastolic septal thickness, end-diastolic posterior wall thickness and left ventricular internal diameter, respectively.

Renal Biopsy

In 4 patients, additional informed consent was obtained,

and renal biopsy was performed within at least 4 mo after

the onset of accelerated hypertension.

Statistical Analysis

Values are expressed as mean ± SEM. For comparisons

within groups at different time points, one-way ANOVA

by repeated measures was performed. A simple regres-

sion analysis was performed for correlations among the

variables. Statistical significance was considered to be

achieved at p < 0.05.

Results

Baseline Characterization of 10 Patients with Acceler-ated Hypertension

Clinical characterization of our patients were listed in Table 1. One woman and 9 men (mean age 42 ± 5) were studied. Mean systolic and diastolic blood pressure were 237 ± 6 and 134 ± 1 mmHg, respectively. Serum creati-nine level was elevated in all patients and mean serum creatinine level was 4.5 ± 0.7 mg/dl. Left ventricular mass index was 150 ± 9 g/m2.

Changes in Blood Pressure after Treatment (Fig. la and b) Figure 1 shows the changes in systolic and diastolic blood

pressure after combined oral administration of calcium antagonist and a~3 blocker. One year after the anti-hypertensive treatment, systolic and diastolic blood pres-sure decreased significantly 141 ± 5 and 90 ± 3 mmHg (p < 0.001). Then at the end of the study, systolic and diastolic blood pressure were stabilized around 128 ± 3 and 79 ± 3 mmHg.

Table 1. Basal Characteristics

ated Hypertension

of Patients with Acceler-

Fig. 1, a: Changes in systolic blood pressure,

in diastolic blood pressure.

b: Changes

162 Hypertens Res Vol. 23, No. 2 (2000)

Changes in Serum Creatinine after Treatment (Fig. 2) Intermittent haemodialysis therapy was . introduced in 5

patients. In these patients, after oral administration of antihypertensive drugs started, serum creatinine levels

gradually decreased. One year later, serum creatinine level decreased to 3.1 ± 0.7 mg/dl (p < 0.05). Except one

patient, renal function of all of these patients was com-pletely recovered to allow withdrawal of haemodialysis therapy. However, during the first one year, another one

patient needed CAPD therapy. And 36 mo later, serum

creatinine

(p<0.01).

level decreased significantly to 2.2 ± 0.4 mg/dl

Echocardiographic Data

After 1 yr of combination treatment with calcium antag-onist and a(9 blocker, LVMI decreased slightly, from 150 ± 9 to 140 ± 9 g/m2, whereas a significant decrease could be observed after 3 years to 128 ± 9 g/m2 (89 ± 12 reduc-tion vs. control) (Fig. 3). Septal and posterior wall thick-ness were reduced significantly by antihypertensive ther-

Fig. 2. Changes in serum creatinine.

Fig. 3. Changes in left ventricular mass index.

Fig. 4. Chan ges in ejection fraction.

Fig. 5. a; Correlation between left ventricular end-dia-stolic diameter and diastolic blood pressure, b: Correlation between left ventricular mass index and diastolic blood

pressure.

Fig. 6. Correlation

blood pressure.

between serum creatinine and systolic

Suzuki et al: End Organ Damage in Malignant HT 163

apy from 15 ± 1 to 12 ± 1 mm and 13 ± 2 to 12 ± 1 mm respectively after 3 yr (both, p < 0.01).

After 3 yr, antihypertensive therapy had significantly reduced both septal and posterior wall thickness, the for-mer from 15 ± 1 to 12 ± 1 mm and the latter from 13 ± 2 to 12±1 mm (both, p < 0.01).

Ejection fraction was significantly increased from 72 ± 3 to 82 ± 4% after 3 years' treatment (p < 0.05, Fig. 4).

Correlations among Variables Highly significant correlations were found between each

pair of LVMI, left ventricular end-diastolic diameter, sep-tal wall thickness, and posterior wall thickness (each, p < 0.0001). The diastolic blood pressure was significantly correlated with the left ventricular end-diastolic diameter

(r = 0.565, p < 0.0001) and with LVMI (r = 0.351, p < 0.05) (Fig. 5a and 5b). The systolic blood pressure was also correlated with the serum creatinine levels (r = 0.515,

p < 0.0005) (Fig. 6).

Renal Biopsy

Typical histopathological changes are shown in Fig. 7.

One of the glomeruli showed fully developed hyperten-

sive glomerulopathy with glomerular capillaries adhered

to each other, and swelling and fatty degeneration of the

endothelial cells. Another glomerulus was largely obliter-

ated with PAS-positive hyalinosis. Diffuse tubular atrophy

and interstitial fibrosis were observed. The characteristic

findings of malignant nephrosclerosis, such as striking "onion peel" thickening of the intima of a small artery

and fibrinoid necrosis of an arteriole at the glomerular

hilus, were not found in any of the specimens obtained

from the 4 patients.

Discussion

In the present study, we confirmed that appropriate blood

pressure control is effective for preserving renal function with amelioration of left ventricular hypertrophy even in

patients with accelerated hypertension. The prognosis of accelerated hypertension remains con-

troversial. Lip et al, have demonstrated that good blood

pressure control was associated with an improved survival rate (23). On the other hand, other workers have sug-

gested that blood pressure control does not necessarily re-duce the incidence of, or progression to, chronic renal fail-ure (24). In addition, the presence of severely impaired renal function has been related to outcomes of patients with accelerated hypertension (25-27). In general, many

patients who develop accelerated hypertension have pre-viously existing essential hypertension (5, 28), although the prevalence of pre-existing renal disease among pa-tients presenting with accelerated hypertension has been variously reported as from 40% (5) to as much as 80%

(3). In patients with chronic glomerulonephritis as an underlying renal disease, IgA nephropathy is the most common cause of accelerated hypertension (29). In the

present study, one patient was documented to have pro-teinuria before onset of accelerated hypertension; howev-er, the other patients did not have a past history of hema-turia and/or proteinuria. Moreover, high blood pressure was noted in more than half the patients prior to the de-velopment of accelerated hypertension. It is therefore un-likely that the patients enrolled in this study had chronic

glomerulonephritis as an underlying renal disease. Fahr (30) provided the first clinical description of de-

compensated benign nephrosclerosis, distinguishing it

Fig. 7. Renal histopathological changes in one o f the patients.

164 Hypertens Res Vol. 23, No. 2 (2000)

from compensated benign nephrosclerosis and from malignant nephrosclerosis. Recently, Ratschek et al. (31) revised these findings. According to their description, the most prominent difference between decompensated be-nign nephrosclerosis and malignant nephrosclerosis lies in the changes in the glomeruli; in decompensated benign nephrosclerosis, hyalinized glomeruli are most common alteration, while in malignant nephrosclerosis, so-called

glomerular loop collapse is the most frequent pathologic change, though such collapse is still quite rare. In decom-

pensated benign nephrosclerosis, postglomerular intersti-tial fibrosis with tubular atrophy is in the foreground of

pathologic changes. These changes are highly similar to the histopathological changes found in 4 of the present

patients. Further, these studies by Fahr and Ratschek et al, provided evidence that these histological changes are found predominantly in male patients. The present cohort included only two female patients, vs. 11 males. It is therefore likely that, in clinical practice, the clinical fea-ture of accelerated hypertension without hemolysis due to destruction of red blood cells, appears as a result of de-compensated benign nephrosclerosis but not as a result of malignant nephrosclerosis. At present, although renal biopsy in patients with accelerated hypertension is gener-ally considered to be less informative than clinical fea-tures and is not carried out unless a diagnosis of lupus nephritis and vasculitis is suspected (32), it is important to remember that similar manifestations appeared from these pathologically different alterations.

The prevalence of left ventricular hypertrophy (LVH) in patients with accelerated hypertension is also con-troversial. In one series (15), LVH was less frequently found, and this lower incidence was attributed to the fact that accelerated hypertension develops abruptly, such that the duration of high blood pressure is insufficient for de-velopment of LVH. On the other hand, other groups have reported variable results for the prevalence of LVH in malignant hypertension (12-14). In the present study, echocardiographic examination was made for all

patients. Moreover, in 3 yr, the LVH of all patients dis-appeared, even in patients maintained on hemodialysis. This provides evidence that LVH would improve with good blood pressure control. Shapiro et al. (12) demon-strated using echocardiography that treatment to reduce blood pressure did not change LVH with resolution of in-coordinate contraction. In their study, no precise anti-hypertensive drug regimen for treatment of malignant hypertension was described. In the present study, all pa-tients were treated with a combination of extended re-lease nifedipine, a long releasing calcium antagonist, and arotinolol, an aj9 blocker. There have been a few reports demonstrating the improvement of cardiac dysfunction with calcium antagonists. Carvedilol has been showing a lot of evidences for improvement of LVH in patients with heart failure and hypertension in a large scale study (20).

Arotinolol has been shown to have a structure similar to carvedilol, and to exert similar actions (18, 19). In light of these findings, the present results revealed that good blood pressure control by means of extended release ni-fedipine and the cardioprotective action of arotinolol can ameliorate LVH and stabilize renal dysfunction.

In our previous study (33), we clearly demonstrated that combination therapy with arotinolol, an a/3 blocker, and nifedipine, an extended release calcium antagonist, is effective for both the reduction of highly elevated blood

pressure and the protection of the kidney. In the present study, we extended this previous investigation to a follow-up of 3 years' duration, and added another important finding, i. e. , that this therapy improved LVH in patients with accelerated hypertension.

At the present time, since decompensated benign nephrosclerosis has been completely forgotten, acceler-ated or malignant hypertension is defined based on clini-cal findings. Also, the underlying or pre-existing renal dis-ease remains uncertain without renal biopsy. We there-fore cannot exclude the possibility that our patients might represent some special population of accelerated-malig-nant hypertension. Second, we might ask why combina-tion treatment with calcium antagonist and aj9-blocker is effective in improving renal dysfunction. Previously, the combination of a a9-blocker and minoxidil, a direct vaso-dilator, was reported to be effective in treatment of pa-tients with malignant hypertension and severe side effects including headache and hypertrichosis (34). Currently, it seems possible that extended release nifedipine might be a suitable substitute for minoxidil. Also, most clinical trials have demonstrated the usefulness of ACE inhibitors in slowing the progression of renal failure and in im-

proving the renal impairment in malignant hypertension (6-8), in spite of few reports supporting the efficacy of calcium antagonists (10). However, it should be noted that the most important intervention for retarding the

progression of renal disease and improving renal function in malignant hypertension is adequate and sustained re-duction of blood-pressure (10). It is therefore reasonable that in the present study the combination treatment pro-duced improvement of renal impairment with good blood

pressure control. Third, it remains controversial whether adequate blood pressure control per se improves LVH or not when antihypertensive agents other than ACE inhibi-tors are applied. In the present study, arotinolol was used instead of carvedilol. This a/3 blocker might be effective for reducing LVH in cooperation with adequate blood

pressure reduction. In conclusion, combination therapy with an extended

release calcium antagonist and a/3 blocker was here shown to be effective in improving the renal and cardiac dysfunction associated with highly elevated blood pres-sure.

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