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ACE-Inhibitor Therapy with Spirapril Increases Nocturnal Hypotensive Episodes in Elderly Hypertensive Patients

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ACE-Inhibitor Therapy with Spirapril Increases Nocturnal Hypotensive Episodes in Elderly Hypertensive Patients Journal of Human Hypertension (2001) 15, 873–878 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE ACE-inhibitor therapy with spirapril increases nocturnal hypotensive episodes in elderly hypertensive patients I Kantola1, A Tere´nt2, M Kataja3 and E Breig-A˚ sberg4 1Department of Medicine, Turku University Central Hospital, Turku, Finland; 2Department of Medicine, Uppsala University Hospital, Uppsala, Sweden; 3National Public Health Institute, Helsinki, Finland; 4Department of Medicine, So¨derhamn Hospital, So¨derhamn, Sweden The purpose of this double-blind, randomised trial with sodes were observed during the antihypertensive treat- a 4-week placebo run-in period followed by an active ment (one in the 3 mg group and 10 in the 6 mg group, treatment period using either spirapril 3 mg or 6 mg P Ͻ 0.01 between the two treatment groups). Fifty-four once a day was to clarify the existence of hypotensive episodes of MAP Ͻ70 mm Hg were observed during the episodes in elderly hypertensive patients treated by an placebo period and 117 during the treatment period ACE-inhibitor. Forty hypertensive patients aged 60–76 (P Ͻ 0.001). During the placebo period low MAPs were years underwent 24-h ABPM at the end of the run-in observed only during night time. During the treatment (week 4) and active treatment (week 9) periods. The period they were seen also from 11 am to 4 pm. In con- mean 24-h systolic blood pressure (SBP) decreased clusion, ACE-inhibitor therapy with spirapril signifi- from 161.9 (26.7) mm Hg to 150.6 (29.9) mm Hg cantly increased hypotensive episodes in elderly hyper- (P Ͻ 0.001) and diastolic blood pressure (DBP) from tensive patients which may worsen their cerebral and 91.70 (14.7) mm Hg to 84.2 (17.3) mm Hg (P Ͻ 0.001). No myocardial circulation episodes of mean arterial pressure (MAP) Ͻ50 mm Hg Journal of Human Hypertension (2001) 15, 873–878 were seen during the placebo period. Instead 11 epi- Keywords: hypotension; ambulatory blood pressure measurement; angiotensin-converting enzyme inhibition Introduction lowest SBP 100–116 mm Hg) compared to dippers (nocturnal SBP fall 13–15%, nocturnal lowest SBP Hypertension, apart from being a risk factor for cor- 116–122 mm Hg). onary artery disease and stroke, causes adaptive cer- In hypertensive patients the occurrence of cardiac ebral vascular changes, leading to a shift of the lower ischaemic episodes could be influenced either by limit of autoregulation towards higher pressure with 1 high BP levels, through an increase of myocardial an impaired tolerance to pressure decrease. In oxygen demand, or by low BP values, through a young and middle-aged effectively treated hyperten- reduction of coronary perfusion due to an upward sive patients, cerebral blood flow autoregulation shift of the lower limit of coronary autoregulation in may or may not be readapted towards normal.1 In the subendocardium.3–5 Pierdomenico et al6 found elderly hypertensive patients non-reversible vascu- nocturnal ischaemia significantly more frequently in lar structural changes would be expected to prevail. non-dippers than in dippers and overdippers among Further, atherosclerotic narrowing of the larger cer- ebral arteries may contribute to impairment of auto- untreated hypertensive patients with coronary regulation by exhausting autoregulatory arteriolar artery disease. Drug therapy significantly reduced dilatation. In fact Kario et al2 have shown in their nocturnal ischaemia in non-dippers, had no signifi- study that the extent of silent cerebrovascular dam- cant effect in dippers and significantly increased age was more severe in extreme dippers (nocturnal night time ischaemia in overdippers. During treat- systolic blood pressure (SBP) fall 21–25%, nocturnal ment, night time ischaemia was significantly more frequent in overdippers than in dippers and non- dippers. Besides the risk of lowering BP too much in eld- Correspondence: Ilkka Kantola, Department of Medicine, Turku erly people, there is also the risk of over-diagnosing University Central Hospital, FIN-20520 Turku, Finland. E-mail 7 ilkka.kantolaȰtyks.fi hypertension. The white-coat effect has been Received 4 June 2001; revised and accepted 12 July 2001 shown to correlate positively with the age of the Nocturnal hypotensive episodes I Kantola et al 874 patient.8 In the study by Kario et al2 the frequency of Procedures silent cerebrovascular damage in the patients with sustained hypertension was greater than that in the Heart rate and BP were registered on three occasions patients with white coat hypertension. during the 4-week placebo phase. Patients entered This study is a part of a Finnish-Swedish efficacy the active treatment phase if office DBP was 100–114 and safety study of spirapril, an ACE-inhibitor, in mm Hg and SBP р200 mm Hg. BP was measured in elderly hypertensive patients. In this part of the the sitting position on the right arm in the morning study 24-h ambulatory BP measurement was perfor- after a 10-min rest, before the intake of placebo or med on the Swedish participants of the study to active drug. The mean value of two measurements clarify the 24-h BP profile of spirapril, especially its was used. nocturnal antihypertensive effects, in elderly hyper- Ambulatory BP measurement was performed at tensive patients. the end of the placebo period and at 5 weeks of spir- april treatment. For ambulatory BP measurement, the Accutracker II (version 30/23, Suntech Medical Subjects and methods Instruments, Raleigh, NC, USA)9 was used. The BP cuff was placed on the left upper arm. The quality Study design of the ambulatory BP measurement was checked by simultaneous auscultatory BP by one of the authors The patients were randomised in a double-blind ˚ fashion to spirapril either 3 or 6 mg for 6 weeks after (EBA). The BP was recorded approximately every a 4-week single-blind placebo wash-out period. The 20 min (randomly distributed by the device within dose remained stable during the period of active the 15–25 min range). The device automatically repeated the measurement if any of the following medication and was taken once daily before break- Ͼ Ͻ fast. were recorded: SBP 220 mm Hg, SBP 80 mm Hg, change of SBP Ͼ50 mm Hg between two measure- ments, DBP Ͼ130 mm Hg, DBP Ͻ40 mm Hg, change of DBP Ͼ40 mm Hg, pulse pressure Ͻ20 mm Hg or Subjects Ͼ110 mm Hg, or pulse pressure change of Ͼ40 Twenty male and 20 female hypertensive patients mm Hg. No values were censored except for the with office diastolic BP (DBP) 100–114 mm Hg and value preceding a repeat measurement. Repeat SBP р200 mm Hg aged 60–76 years were recruited. values outside these limits were not excluded from Patients with a myocardial infarction within the pre- the statistical analyses in order not to miss true vious 6 months, severe or unstable angina pectoris, values at the extremes. congestive heart failure, non-controlled diabetes According to the study protocol, patients were mellitus, renal artery disease or arrhythmias were classified as responders if the office DBP was р90 not included. mm Hg or decreased by у10 mm Hg during the Eighteen patients, seven men and 11 women, were active treatment phase. randomised to the 3 mg dose, and 22 patients, 13 According to the ambulatory BP measurement the men and nine women, to the 6 mg dose. Baseline patients were classified as hypertensives if either characteristics of the patients are given in Table 1. their average daytime SBP was Ͼ140 mm Hg or aver- The patients did not have either coronary heart dis- age night time SBP Ͼ120 mm Hg or average daytime ease or cerebral artery disease. Other antihyperten- DBP Ͼ90 mm Hg or average night time DBP Ͼ80 sive agents, long-acting nitrates, beta-adrenergic mm Hg (the recommendations of the University of blocking agents, calcium-channel blocking agents, Connecticut Group).10 Patients who fulfilled the diuretics, MAO-inhibitors, tricyclic antidepressants, office criteria for inclusion, but had normal ambulat- tranquilizers, lipid-lowering agents and potassium ory BP measurement curves, were classified as supplements were prohibited. white-coat hypertensives. Table 1 Baseline characteristics of the patients. Mean (s.d.) Spirapril 3 mg Spirapril 6 mg Total (n = 18) (n = 22) (n = 40) Age (yrs) 66.3 (4.6) 65.0 (3.3) 65.6 (4.0) Body weight (kg) 77.8 (11.6) 80.5 (12.2) 79.3 (11.8) Height (cm) 168.2 (9.0) 171.0 (10.0) 169.8 (9.6) SBPa (mm Hg) 161.9 (8.1) 161.0 (10.2) 161.4 (9.2) DBPa (mm Hg) 102.4 (3.1) 104.1 (3.2) 103.3 (3.3) Heart ratea 79.9 (9.7) 78.3 (13.1) 79.0 (11.6) aAfter 10 min in the sitting position at the end of the placebo period. Journal of Human Hypertension Nocturnal hypotensive episodes I Kantola et al 875 The definition of a low BP in this study was MAP Ͻ50 mm Hg (critically low), corresponding to the lower limit of cerebral autoregulation in healthy per- sons; and MAP Ͻ70 mm Hg (low), representing the lower limit of cerebral autoregulation in hyperten- sive patients.1,11 The MAP for each measurement was automatically calculated by the Accutracker II equipment. Safety Adverse events were checked on four occasions evenly spread throughout the study period. Any change in the patient’s condition, even a common cold or shoulder pain, was noted as an adverse event, irrespective of whether a casual relationship to drug therapy was plausible or not. Figure 1 Smoothed (three-point moving median) curves showing the placebo-subtracted antihypertensive effect of active treatment with spirapril, 3 mg and 6 mg (all 40 patients).
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