An Effective Approach for Treating Elderly Patients With Isolated Systolic Hypertension: Results of an Italian Multicenter Study With Fosinopril

Abstract

Cardiovascular diseases are the most common causes of mortality, and hypertension is the most common cardiovascular disease in all ages. The Systolic Hypertension in the Elderly Program (SHEP) trial has shown that the pharmacologic reduction of isolated systolic hypertension can significantly reduce the incidence of cardiovascular complications.

The aim of the Italian multicenter study reported here is to compare the efficacy, safety, and tolerability of fosinopril, a novel angiotensin converting enzyme (ACE) inhibitor with a dual route of excretion, with chlorthalidone, the diuretic administered in the SHEP study, in 312 elderly patients with isolated systolic hypertension.

Our results show that fosinopril and chlorthalidone produce identical and statistically significant reductions in systolic blood pressure (−23.9 ± 11.6 mm Hg and −23.7 ± 10.9 mm Hg, respectively) and, to a lesser extent, in diastolic blood pressure (−7.1 ± 3.1 mm Hg and −5.2 ± 2.3 mm Hg, respectively). Only chlorthalidone caused a statistically significant change in uric acid, total cholesterol, blood urea, and serum potassium concentrations. Fosinopril was also somewhat better tolerated than chlorthalidone.

In conclusion, the novel ACE inhibitor fosinopril is an effective and well-tolerated antihypertensive agent for use in elderly patients with isolated systolic hypertension and appears to be a suitable alternative for the treatment of isolated systolic hypertension. Am J Hypertens 1997;10:230S–235S © 1997 American Journal of Hypertension, Ltd.

Isolated systolic hypertension, angiotensin converting enzyme inhibitors, fosinopril, elderly patients

Cardiovascular disease is the most common cause of mortality, and hypertension is one of the most common predictors of serious cardiovascular disease.¹ The advent of effective and well-tolerated antihypertensive agents has prompted many intervention studies in hypertensive patients. These studies have shown consistently a statistically significant reduction in cardiovascular events in treated hypertensive patients when compared with a placebo control group,^2,3 offering evidence for the beneficial effect of pharmacologic reduction of elevated blood pressure. However, in many of these intervention studies, elderly hypertensive patients were either excluded or formed only a small cohort of the randomized patients and therefore, it is not possible to extend the conclusion of these studies to the elderly. In addition, a diastolic blood pressure ≥90 to 95 mm Hg was usually set as the inclusion criterion for the study or as the titration threshold for the administration of drugs or placebo.

As a consequence of these limitations in previous epidemiologic studies, the importance of either systolic–diastolic or isolated systolic hypertension in elderly arterial hypertension, has been the subject of numerous debates and publications. Doubt has been expressed about the clinical importance of blood pressure elevation in the elderly and concerns raised about the hemodynamic consequences of reducing elevated blood pressure in this population. According to epidemiologic studies, it appears that the course of arterial pressure in the aging population is characterized by progressive elevation of systolic blood pressure until the last decades of life, whereas diastolic blood pressure reaches a plateau in the sixth decade of life and then remains stable or eventually decreases thereafter. The time course for this blood pressure profile is attributable, to a large extent, to a loss of compliance in the aorta and large arteries.⁴ For this reason, blood pressure elevation with aging has been considered a compensatory mechanism to supply the body's organs with sufficient blood. If this were true, lowering blood pressure would be contraindicated and even dangerous, particularly in patients with isolated systolic hypertension.

The clinical relevance of isolated systolic hypertension has been noted in two observational epidemiologic studies^5,6 and in a multicenter pharmacologic trial.⁷ The observational studies have shown that high systolic blood pressure is a much greater risk factor for cardiovascular complications than high diastolic blood pressure and that the clinical importance of systolic pressure as a risk factor increases with aging (Fig. 1). ^5,6

Fitted incidence of cardiovascular disease by level of systolic blood pressure (minimum, mean, or maximum of three readings). Men ages 45 to 74 years, age-adjusted incidence. Framingham Heart Study (Reproduced from Kannel et al,¹ with permission.)

Figure 1.

The effects of the pharmacologic reduction of blood pressure on cardiovascular events in elderly patients with isolated hypertension was specifically evaluated in an American multicenter study (Systolic Hypertension in the Elderly Program, SHEP),⁷ which showed a statistically significant reduction in cardiovascular complications in treated elderly patients. Furthermore, the benefits of antihypertensive treatment for systolic hypertension appeared similar to those found in elderly patients with systolic–diastolic hypertension.^8–10

New classes of antihypertensive drugs have become available for the treatment of arterial hypertension during the past decades, but none has been compared with placebo to evaluate the effect on cardiovascular complications.

Fosinopril, a third generation angiotensin converting enzyme (ACE) inhibitor is structurally different from previous ACE inhibitors and is characterized by a dual (renal and hepatic) and compensatory route of excretion.¹¹ Its antihypertensive efficacy and tolerability have been demonstrated in a study of young and adult patients with mild-to-moderate arterial hypertension.¹² With the increasing use of ACE inhibitors with their proven cardioprotective properties, it is important to study the efficacy and tolerability of such inhibitors. The aim of this short-term study was to demonstrate the improved efficacy and tolerability of fosinopril with a diuretic, chlorthalidone, in elderly patients with isolated systolic hypertension.

Material and Methods

Men and women more than 60 years of age with seated systolic blood pressure of 160 to 200 mm Hg and seated diastolic blood pressure of less than 95 mm Hg at the end of a 5-week placebo run-in period were admitted to the study. An orthostatic diastolic blood pressure >65 mm Hg was also required for admission. Patients were excluded if they had secondary forms of isolated systolic hypertension, grade III–IV hypertensive retinopathy, clinical heart failure, recent myocardial infarction or stroke, serum creatinine >1.5 mg/dL, proteinuria >500 mg/24 h, uncontrolled diabetes mellitus, or hepatic insufficiency.

This was a multicenter, double-blind, parallel group study. After a 5-week placebo run-in period, patients meeting all admission criteria with no exclusion criteria were randomized to 10 mg of fosinopril or 12.5 mg of chlorthalidone administered orally. After 4 weeks of active treatment, the doses of fosinopril or chlorthalidone were doubled if seated systolic blood pressure was not <160 mm Hg or lowered by at least 20 mm Hg. The total period of active drug therapy was 9 weeks.

The reference blood pressure for admission to the study and for titration of study medications was that measured in the seated position after a 5-min rest with the arm positioned at heart level. In addition, blood pressure measurements were performed in both the supine and standing positions.

Blood pressure was measured using a mercury sphygmomanometer 22 to 26 h after administration of placebo or active drug. On the first day of active treatment and later, on the first day of doubling the dose of active drugs in nonresponders, blood pressure was measured hourly for 4 h after oral administration. Each blood pressure value was calculated as the average of three measurements.

A blood sample was taken at the end of the placebo run-in period and after active drug administration for measurement of hemoglobin, white blood cells, platelets, total bilirubin, total cholesterol, serum transaminases, plasma sodium and potassium, serum creatinine, uric acid, and blood glucose levels. A urinalysis and electrocardiogram were performed also before and after treatment.

Results

The principal demographic characteristics of the patients randomized at the end of the placebo period to fosinopril (n = 150) or chlorthalidone (n = 162) are shown in Table 1.

Table 1

Demographic Characteristics of Patients Randomized to Fosinopril and Chlorthalidone

Characteristics	Fosinopril (n = 150)	Chlorthalidone (n = 162)
Age (y)	69.4 ± 6.9	71.1 ± 6.5
M/F (%)	43/57	42/58
BMI	30.7 ± 8.7	31.7 ± 10.4
Systolic BP (mm Hg)	173.3 ± 11.8	175.0 ± 9.0
Diastolic BP (mm Hg)	85.5 ± 6.8	84.8 ± 6.7
Heart rate (beats/min)	75.0 ± 9.1	73.2 ± 9.4
Abnormal ECG (%)	59.3	58.0
Blood glucose (mg/dL)	102.8 ± 33.2	103.0 ± 20.7
Total cholesterol (mg/dL)	217.0 ± 42.2	219.1 ± 40.0
Uric acid (mg/dL)	5.1 ± 1.3	5.2 ± 1.4
Serum K (mEq/L)	4.3 ± 0.4	4.3 ± 0.5
Serum creatinine (mg/dL)	1.0 ± 0.2	1.0 ± 0.2

P not significant for all characteristics.

BMI, body mass index; BP, blood pressure; ECG, electrocardiogram.

There were no statistically significant differences between the two groups. The patients in both groups had mild-to-moderate isolated systolic hypertension and were slightly overweight. At the end of 9 weeks of active treatment, there were similar reductions in systolic blood pressure in both groups, which were statistically significant when compared to baseline values (−23.9 ± 11.6 mm Hg in the fosinopril group and −23.7 ± 10.9 mm Hg in the chlorthalidone group; P < .001 v placebo). Diastolic blood pressure was reduced slightly in both groups (−6.1 ± 3.1 mm Hg in the fosinopril group and −5.2 ± 2.3 mm Hg in the chlorthalidone group; P < .01 v placebo). At the end of the study, 69% of patients in the fosinopril group were receiving 10 mg orally and 31% 20 mg orally; in the chlorthalidone group, 66% of patients were treated with 12.5 mg and 34% with 25.0 mg. There was no difference in the percentage of patient responders or patients normalized (60% in both groups). Heart rate was unchanged in both groups for the entire duration of the study.

During the 4 h after either the initial administration of fosinopril or chlorthalidone (Table 2), or the doubling of doses in nonresponders, there was a mild progressive reduction in systolic and diastolic blood pressures with no side effects.

Table 2

Time Course of Changes in Seated Systolic and Diastolic Blood Pressure During the First 4 h After Oral Administration of 10 mg of Fosinopril and 12.5 mg of Chlorthalidone

		Hour
	Baseline	1	2	3	4
Systolic blood pressure
Fosinopril	173 ± 12	170 ± 13	166 ± 13	163 ± 13	163 ± 13
Chlorthalidone	175 ± 9	171 ± 12	167 ± 13	165 ± 14	164 ± 14
Diastolic blood pressure
Fosinopril	85 ± 7	84 ± 6	83 ± 6	81 ± 6	81 ± 6
Chlorthalidone	85 ± 7	84 ± 7	82 ± 7	81 ± 7	81 ± 7

Values are means ± SD.

Mean changes in systolic and diastolic blood pressure and heart rate secondary to positional change were minor before and after drug treatment (Table 3). However, if we consider individual patients, a total of 47 patients (22 in the fosinopril group and 25 in the chlorthalidone group) had a reduction of systolic blood pressure >20 mm Hg and/or of diastolic blood pressure >10 mm Hg when standing up from the supine position, but only one of these patients complained of symptoms of orthostatic hypotension.

Table 3

Orthostatic Changes in Systolic (SBP) and Diastolic (DBP) Blood Pressure and in Heart Rate (HR) at Baseline and After Treatment in Fosinopril- and Chlorthalidone-Treated Patients

	Fosinopril	Chlorthalidone
Baseline
SBP	−0.9 ± 8.3	−1.6 ± 8.6
DBP	+0.3 ± 6.2	−0.2 ± 5.5
HR	+4.1 ± 5.7	+4.1 ± 9.5
Treatment
SBP	−2.8 ± 7.9	−2.8 ± 9.4
DBP	−0.1 ± 5.4	+0.1 ± 7.3
HR	+4.4 ± 8.0	+4.1 ± 5.1

+, increase in mm Hg; −, decrease in mm Hg.

Values are means ± SD.

Laboratory tests showed a statistically significant (P < .05) increase in uric acid (from 5.2 ± 1.4 to 5.7 ± 1.4 mg/dL), blood urea (40.3 ± 11.4 to 42.7 ± 12.9 mg/dL), and total cholesterol (from 219 ± 40 to 230 ± 42 mg/dL) in the chlorthalidone-treated group when compared to baseline, but no significant changes were found in the fosinopril-treated group. At the end of the treatment period, uric acid, blood glucose, and total cholesterol levels were significantly higher and serum potassium significantly lower in the chlorthalidone-treated group when compared with the fosinopril-treated group (Table 4).

Table 4

Biochemical Parameters After Treatment in the Fosinopril- and Chlorthalidone-Treated Groups

Parameters	Fosinopril	Chlorthalidone	P
Hemoglobin (g/dL)	13.9 ± 1.2	13.9 ± 1.3	NS
Blood urea (mg/dL)	40.4 ± 10.7	42.7 ± 12.9	NS
Serum creatinine (mg/dL)	1.0 ± 0.2	1.0 ± 0.2	NS
Uric acid (mg/dL)	5.1 ± 1.3	5.7 ± 1.4	<.001
Blood glucose (mg/dL)	100 ± 26	106 ± 29	.037
Total cholesterol (mg/dL)	215 ± 41	230 ± 42	.002
Serum K (mEq/L)	4.4 ± 0.7	4.1 ± 0.4	.016

The incidence of adverse events was significantly higher in the chlorthalidone-treated group (16%) when compared with patients receiving fosinopril (6.7%); low serum potassium levels and increase in serum transaminase concentrations were the most frequently reported adverse events. In total, only 7 of 150 (4.7%) patients in the fosinopril-treated group and 8 of 162 (4.9%) patients in the chlorthalidone-treated group withdrew from the study. It is of interest that no patient in the fosinopril group withdrew because of cough.

Discussion

The aim of antihypertensive treatment is to reduce the incidence of cardiovascular complications; this goal is reached by reducing elevated blood pressure levels. However, although the effects of antihypertensive treatment on blood pressure are apparent in the short term, the benefit in reducing the number of cardiovascular events only becomes evident after years of treatment.¹ A recently published article on the Framingham study¹³ has shown that the benefits can be even greater than those observed in Collins' metaanalysis¹ if the study is of longer duration.

In our short-term study, fosinopril has been shown to be an effective agent for treatment of elderly patients with isolated systolic hypertension. Indeed, 10 mg of fosinopril in the majority of patients and 20 mg of fosinopril in the remainder caused a statistically significant reduction in systolic blood pressure similar to that found in the chlorthalidone-treated group. As expected, the reduction of diastolic blood pressure with fosinopril and chlorthalidone was less than that of systolic blood pressure.

Fosinopril, like chlorthalidone, caused a progressive reduction in blood pressure beginning with the first dose or after doubling the dose in initial nonresponders.

Because the prevalence of orthostatic hypotension is higher in the elderly than in the pediatric and general adult populations, and as some antihypertensive agents can cause or exacerbate this clinical condition, in this study blood pressure was measured when patients were supine, seated, and standing. Forty-seven patients in the study had orthostatic hypotension (22 in the fosinopril group and 25 in the chlorthalidone group) by the definition used.

Fosinopril was well tolerated; only 6% to 7% of patients complained of side effects, and of these only seven withdrew from the study, whereas the incidence of adverse events was 16% and the number of drop-outs was eight in the chlorthalidone group. Therefore, the total number of adverse events was higher in the diuretic-treated group.

None of the laboratory tests was significantly different from baseline in patients treated with fosinopril, whereas uric acid, blood urea, and total cholesterol levels were significantly elevated after chlorthalidone therapy when compared with the baseline period and with the fosinopril-treated group (Table 4).

To obtain a more meaningful clinical evaluation of fosinopril in the treatment of elderly patients with isolated systolic hypertension (ISH), we believe that a comparison with the SHEP study⁷(the only interventional epidemiologic trial performed to date in elderly patients with ISH), needs to be made.

If, as suggested in the World Health Organization/International Society of Hypertension (WHO/ISH)¹⁴ guidelines for hypertension, the benefit of antihypertensive treatment shown in the intervention trials is attributable to blood pressure reduction per se rather than to the effect of any specific class of agents, fosinopril should be considered an appropriate alternative to diuretic drugs for the treatment of elderly patients with isolated systolic hypertension. If we compare the reduction in systolic blood pressure that resulted from fosinopril therapy in our study to that from chlorthalidone therapy in the SHEP trial (Table 5), there is clearly no difference in the antihypertensive effect of treatment between the ACE inhibitor and the diuretic. Only diastolic blood pressure was slightly lower in the SHEP study. This could have been attributable to the use of a chlorthalidone–atenolol combination in about 50% of the patients in the active treatment arm of the SHEP trial, whereas in our study fosinopril was used as monotherapy. Therefore, as far as antihypertensive efficacy is concerned, fosinopril can be considered to be a suitable alternative to diuretics for the treatment of patients with isolated systolic hypertension.

Table 5

Changes in Systolic and Diastolic Blood Pressure in the Fosinopril in Isolated Systolic Hypertension (FISH) and SHEP Studies (mm Hg)

	Italian (FISH) Study		SHEP Study7
	Fosinopril	Chlorthalidone	Fosinopril	Chlorthalidone
Systolic blood pressure	−24	−24	−26	−15
Diastolic blood pressure	−6	−5	−9	−4

Furthermore, among the different hypotheses put forward to explain the lower than expected prevention of ischemic heart complications in treated hypertensive patients, the metabolic hypothesis attributes the partial cardioprotection to the effects of diuretics, and to a lesser extent, β-blockers on lipid, carbohydrate, and electrolyte metabolism, including the effects on insulin sensitivity. If this were true, fosinopril would be more than just an alternative to diuretic treatment for arterial hypertension. As our own and other studies show, fosinopril can be considered metabolically neutral, because it does not interfere with plasma lipid, plasma glucose, serum electrolytes, or insulin sensitivity. ACE inhibitors are better tolerated and have increased compliance than diuretics in real practice.¹⁵ In addition, ACE inhibitors have proven cardioprotection and event reduction in patients with heart failure, after myocardial infarction, diabetes, and nephropathy.

In addition fosinopril's dual compensatory route of excretion, which prevents accumulation of the drug in patients with compromised renal function, so common in elderly hypertensives, provides additional benefits in patients with ISH.

Several large randomized trials have demonstrated the cardioprotective properties of ACE inhibitors. This trial confirms the highly efficacious ability of fosinopril to lower systolic blood pressure, as well as a diuretic recognized as excellent in this area. Fosinopril is an effective and well-tolerated antihypertensive agent for use in elderly patients with isolated systolic hypertension and appears to be a suitable alternative for the treatment of isolated hypertension.

APPENDIX

Investigators and Participating Centers Alicandri C., Brescia; Ambrosoli S., Fidenza; Baduini G., Torino; Bellini G., Trieste; Borghetti A., Parma; Cadel A., Monza; Carbonin P.U., Roma; Circo A., Catania; Cardoni O., Gubbio; Colonna A., Casarano (LE); Corallo S., Milano; Corradi L., Broni (PV); De Cesaris R., Bari; Di Taranto A., Foggia; De Venuto R., Trento; Federighi G., Pistoia; Finardi G., Pavia; Giusti L., Pisa; Irace L., Cerreto Sannita (BN); Lechi A., Verona; Licata G., Palermo; Lucatti A., Genova; Maggi G., Stradella (PV); Masotti G., Firenze; Pirrelli AM., Bari; Polese A., Milano; Policicchio D., Moneforte (AV); Ravera B., Salerno; Rengo F., Napoli; Rossi P., Fuvizzano (MS); Rotiroti D., Avellino; Santilli D., Nemi (RM); Senin U., Perugia; Terzoli L., Seregno; Timio M., Foligno; Venco A., Varese; Zonzin P., Rovigo.