Assessment of Single Versus Twice Daily Dosing of Ramipril by Ambulatory Blood Pressure Monitoring in Patients Similar to Those Included in the HOPE Study

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Journal of Human Hypertension (2007) 21, 525–530 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study

D Goyal1, AY Chong1, RL Watson1, N Prasad2 and RD Watson2 1University Department of Medicine, City hospital, Birmingham, UK and 2Department of Cardiology, City Hospital, Birmingham, UK

Ramipril has been used in twice daily dose of 5 mg in ramipril causes a significant reduction of BP over 24-h most heart failure trials, whereas the dose used in Heart period as compared with baseline. The mean baseline Outcomes Prevention Evaluation (HOPE) study was ABP was 124/73 mm Hg, which reduced to 117/69 mm Hg 10 mg once at bedtime. The HOPE investigators in an for the twice-a-day regimen (Po0.001) and 115/68 mm ambulatory blood pressure (ABP) substudy observed a Hg for the once a day regimen (Po0.001). Both regimes fall of nighttime but not daytime blood pressure (BP). effectively lower BP to a similar extent. Ramipril causes We examined the effects of once daily ramipril 10 mg significant BP reduction in both once- and twice-daily versus 5 mg twice a day. Twenty-nine patients were dosing. The fall in BP after daytime dosing is greater recruited based on the original criteria for the HOPE than that observed in the HOPE study (including ABP study and were given ramipril either in twice-daily dose substudy). Once-daily dosing in the morning seems (5 mg b.d.) or once daily (10 mg o.d.) each morning in to be effective in causing a significant reduction in the randomized, prospective crossover trial. Twenty-four ABP profile of patients at high-risk of a future vascular hour ABP recordings were taken just before commence- event. ment of ramipril therapy and after treatment with twice- Journal of Human Hypertension (2007) 21, 525–530; daily and once-daily ramipril. Our results show that doi:10.1038/sj.jhh.1002174; published online 26 April 2007

Keywords: ambulatory blood pressure; ramipril; angiotensin-converting enzyme inhibitors

Introduction that degree.2 However, more recently even small differences in OBP as observed in the Anglo- Several studies have shown that angiotensin- Scandinavian Cardiac Outcomes Trial study be- converting enzyme (ACE) inhibitors improve survi- tween different treatment regimes may translate into val in patients with left ventricular dysfunction. The significant differences in outcome.3 Therefore, Heart Outcomes Prevention Evaluation (HOPE) 1 clearer definition of the effect of treatment by study, however, showed that in patients aged studying ambulatory blood pressure (ABP) profile 55 years or older, with high risk of cardiovascular may provide clearer insight into possible benefits of events and without evidence of left ventricular BP lowering. dysfunction, ramipril significantly reduced the risk The parent compound of ramipril has an elimina- of death, myocardial infarction and stroke. The tion half-life of 1–5 h in healthy volunteers.4,5 Its effect was not thought to be due to BP lowering metabolites have an elimination half-life of 13–17 h per se as the office blood pressure (OBP) fell by an 1 with daily doses of 5–10 mg. However, with smaller average of 3/2 mm Hg only. Indeed, the beneficial doses of 1–2 mg, the elimination half-life is longer effects seen in HOPE was calculated to be around ranging from 35 to 60 h, and is thought to be due to three times than that expected of a decrease of BP of the binding/dissociation kinetics of the ramiprilat/ ACE complex. The half-life is also significantly Correspondence: Dr D Goyal, University Department of Medicine, increased in the elderly and in the presence of renal City hospital, Dudley Road, Birmingham B18 7DQ, UK. impairment.5–7 E-mail: [email protected] Previous studies on the effects of ramipril in heart This paper was dealt with by a Guest Editor, Associate Professor failure have shown that ramipril resulted in a Bernard Cheung from the University of Hong Kong, and editorial 8 decisions were independent of the Birmingham-based editor. reduced mortality. However, the target dose of Received 9 April 2006; revised 19 January 2007; accepted 28 ramipril used was 5 mg twice daily. In the HOPE January 2007; published online 26 April 2007 study, the benefits observed were deemed out of Assessment of single versus twice daily dosing of ramipril by ABP D Goyal et al 526 proportion to the reduction in OBP. However, in a ments. A variable number of OBP readings were substudy of the HOPE study utilizing 24 h ABP obtained to ensure that patient does not have measurement, a significant reduction in 24 h ABP uncontrolled hypertension. After recruitment a measurement was demonstrated, more pronounced minimum of one BP reading was made as it was during the night after ramipril was given once daily recorded to assess patient safety for continuation at bedtime. The authors of this substudy suggested of trial. that the beneficial effects of ramipril on cardiovascular morbidity and mortality might be at least partly attributed to BP lowering.9 ABP measurement ABP monitoring profiles BP over a 24-h period ABP values were obtained using a non-invasive and has been shown to correlate more accurately oscillometric system (SpaceLabs 90207, SpaceLabs, with target organ damage than clinic mercury Inc). An experienced nurse or a technician fitted the sphygmomanometer readings10 and it provides device to the patient. Patients were instructed not to additional information such as BP load, BP varia- restrict their daily activities during the monitoring bility and nocturnal BP profile.11 periods. BP and heart rates were recorded auto- The objective of this study was to assess the matically every 20 min during the daytime (07.00– duration of effect of ramipril treatment on the BP in 23.00 h) and at 30 min interval during the night time normotensive patients similar to those in the HOPE (23.00–7.00 h). We averaged readings over an hour to study when the treatment is administered either give a single hourly reading, therefore reducing the once daily in the morning or twice daily. ABP effect of any missing data. Means were calculated monitoring in these patients may provide evidence for the whole 24-h period and for three 4 h of a significant effect on BP due to ramipril therapy periods between (24:00–15:00 h, 01.00–04.00 h and that is not reflected by office mercury sphygmoman- 05.00 h–08.00 h). ometer readings and which may have contributed in The patients selected were not on any ACE- part to the beneficial effects of ramipril seen in the inhibiting medication at the time of recruitment. HOPE study. There was a run-in period of a week. After that, patients were initiated on ramipril 2.5 mg once daily for 1 week and their renal function was subse- Methods quently monitored. Patients were subsequently randomised to either 5 mg ramipril in once-daily Study participants dose in the morning or 2.5 mg ramipril in twice- Patients were recruited based on the original inclu- daily dose. After a 3-week-period, the dose of sion and exclusion criterion for the HOPE study.1 ramipril was uptitrated to 10 mg either as a once- Briefly, people with and without diabetes were daily dose in the morning, or as a 5 mg twice-daily recruited, who were aged 55 years or older, and dose to be given at 10.00 and 22.00 h. Drawing out a who had a history of cardiovascular disease (coronary card blindly to allocate patients to treatment with artery disease, stroke or peripheral vascular disease) once- or twice-daily treatment regimes initially did or diabetes plus at least one other cardiovascular risk randomization. Eventually, all of these patients were factor (total cholesterol 45.2 mmol/l, high-density then crossed over to receive ramipril in the lipoprotein-cholesterol oo0.9 mmol/l, hypertension, alternative ramipril dose (either 5 mg twice a day known microalbuminuria or current smoking). Key or 10 mg once daily in the morning). There was no exclusion criteria were dipstick-positive proteinuria washout period between the two dosing regimens as or established diabetic nephropathy, other severe we were comparing the same drug in same total renal disease, hyperkalemia, congestive heart fail- dosage and moreover, the ABP recordings were ure, low-ejection fraction (o60%), uncontrolled taken 3 weeks after the crossover. Their BP was hypertension (all patients had a clinic BP of o160/ monitored with a 24-h ABP recording just before 90 mm Hg), recent myocardial infarction or stroke commencement of ramipril, week 8 (3 weeks after (o4 weeks) and use of or hypersensitivity to vitamin maximum tolerated dose) and week 11 (3 weeks E or ACE inhibitors. after crossover) as shown in Table 1. The local research ethics committee based at the Sandwell and West Birmingham approved the study. The study was carried out at a single centre Statistics in a prospective crossover trial. Informed consent Power calculations were derived from the study by was obtained from all the patients. Coates et al.12 on ABP monitoring in the assessment of antihypertensive treatment. In a sequential trial for a power of 0.8 (Po0.05), the number of patients OBP needed to detect a difference of 5 mm Hg in systolic OBP was recorded by an experienced nurse in the blood pressure (SBP) between two treatment groups sitting position after 15 min of rest. The BP was is 27 for an ABP study. Similarly, for a difference of checked using an automated OMRON manometer. 3 mm Hg, in diastolic blood pressure (DBP) the The same arm was used for OBP and ABP measure- number needed for a similar powered trial was 35.12

Journal of Human Hypertension Assessment of single versus twice daily dosing of ramipril by ABP D Goyal et al 527 Table 1 Flow chart of the plan of investigation

Week 0 Week 1 Week 2a Week 5b Week 8c Week 11

ABPM day 6 2.5 mg ramipril o.d. 2.5 mg ramipril b.d. 5 mg ramipril b.d. 10 mg ramipril o.d. ABPM ABPM day 6 2.5 mg ramipril o.d. 5 mg ramipril o.d. 10 mg ramipril o.d. 5 mg ramipril b.d. ABPM

Abbreviations: o.d., once a day; b.d., twice a day. aRandomized to either ramipril 2.5 mg twice a day or 5.0 mg once a day. bUptitrated to higher dose. cABPM before crossover to alternative dose.

Results are presented as mean7standard deviation Table 2 Baseline characteristics of participants unless otherwise stated. Statistical analysis was 7 performed with the Minitab program package. Mean age 61.07 7.30 Sex Male 22 (81.5%), female 5 (18.5%) Paired t-test for independent samples were used to Ethnic origin Caucasians 24 (88.9%), test differences between groups before and after Asians 3 (11.1%) treatment with ramipril. A value of Po0.05 was Coronary artery disease 27 (100%) considered significant. Peripheral vascular disease 2 (7.4%) Diabetes 5 (18.5%) Smokers 2 (7.4%) Hypertension 6 (22.2%) Results Hyperlipidaemia 10 (37%) Baseline mean ambulatory 123.7 (14.7) Thirty-two patients fulfilled the inclusion criteria systolic pressure (s.d.) Baseline mean ambulatory 73.3 (9.1) and after consent were initiated on ramipril therapy. diastolic pressure (s.d.) Three patients discontinued owing to adverse Baseline mean office blood 133/81 mm Hg reaction to ramipril therapy. Two of them developed pressure (s.d.) dry cough and the third patient reported dizziness Baseline creatinine 87.50712.35 on treatment with ramipril. Adequate recordings with 480% recordings were available in 27 out of the 29 subjects studied who were considered for analysis. One out of these 27 patients did not Table 3 Concomitant medications of the 27 randomised patients tolerate the top dose of ramipril 10 mg once a day or 5 mg twice a day and his ABP profile was Medication Number of patients Percentage of patients assessed using the dose of 2.5 mg twice a day versus b-Blockers 17 63.0 5 mg once a day. Calcium antagonists 14 51.9 Baseline characteristics of these 27 patients Diuretics 6 22.2 studied are shown in Table 2 and the concomitant Oral nitrates 8 29.6 medications at the time of randomization are shown Aspirin 24 88.9 in Table 3. One patient had a reduction in the dose Clopidogrel 5 18.5 Statins 25 92.6 of b-blockers during the course of this study owing to symptomatic bradycardia. All other patients had no adjustment of their antihypertensive therapy during this period. There was a reduction in the Systolic Blood pressure variation over 24 hours ambulatory SBP and DBP profile of these patients 140 when treated with ramipril given either in a 5 mg 130 twice-daily dose or 10 mg once daily in the morning 120 as compared with the baseline ABP (Figures 1 and 110 2). The average SBP was 123.7 mm Hg at baseline and fell to 116.9 mm Hg on the twice-daily dose and 100 Baseline BD dose 90 115.1 mm Hg on the once-daily dose (P-values OD dose o0.001 for both values). Similarly, the DBP was Blood pressrue (mmHg) 80

73.3 mm Hg at baseline and fell to 69.3 mm Hg on 2 4 6 8 the twice-daily dose and 68.3 mm Hg on the once- 10 12 14 16 18 20 22 24 Time daily dose (P-value o0.001 for both values). There OD- Once a day dose BD- Twice a day dose was no difference (P ¼ NS), however, between the once-daily and the twice-daily dosage regimens. We Figure 1 Mean systolic ABP profile. o.d. – once-a-day dose; b.d. further analysed the difference in the BP profile at – twice-a-day dose. 2–6, 15–18 and 19–22 h after ramipril therapy as a reflection of the peak and trough effects of ramipril. dosages as compared with baseline at each of the These data again showed that there was a significant different time intervals (Tables 3 and 4). There was a reduction of ABP with both once- or twice-daily trend to better BP control with once-daily dosing as

Journal of Human Hypertension Assessment of single versus twice daily dosing of ramipril by ABP D Goyal et al 528 compared with twice-daily dose of ramipril, but the Discussion difference was not statistically different. However, we also demonstrated a waning of the effect of Our study showed a significant drop in both ramipril on DBP after 19–22 h of administration in a daytime and nighttime BP when patients were single daily dose regime (decrease in ambulatory treated with ramipril either in 10 mg daily dose (in diastolic BP no longer statistically significant, the morning) or 5 mg twice daily. The average 24 h P ¼ 0.57). BP dropped by 8.6/5.0 mm Hg on treatment with Therapy with ramipril did not cause any signifi- ramipril in 10 mg once-daily dose administered in cant reduction in the OBP profile (Tables 2 and 3). the morning as compared with 6.8/4.0 mm Hg when There was no significant change in either serum treated with 5 mg ramipril twice daily. ABP HOPE potassium or creatinine after treatment with substudy showed a significant drop in the night ramipril. The mean pretreatment serum potassium time BP but did not show any difference in the 7 daytime BP probably due to the bed time dosing and was 4.3 0.3 mmol/l and after treatment was 9 4.370.3 mmol/l. The serum creatinine was 87712 the small number of patients studied. The average and 89715 mmol/l before and after treatment. 24-h BP was reduced by 10.0/6.6 mm Hg in their study, which is comparable to the reduction seen in our study along with a recently published study Diastolic blood pressure variation over 24 hours comparing the effect of treatment with ramipril 85 versus diltiazem on the ABP profile.13 80 The fall in OBP was not significant when patients 75 were treated with either once-or twice-daily regime 70 of ramipril. This was in keeping with the small 65 reduction of 3/2 mm Hg in OBP as seen in the HOPE study (Tables 5 and 6). OBP were reduced by only 5/ 60 Baseline BD dose 2 mm Hg on treatment with perindopril in the 55 OD dose European Trial on Reduction of Cardiac Events with Blood pressure (mmHg) 50 Perindopril in Patients with Stable Coronary Artery 2 4 6 8 14 10 12 14 16 18 20 22 24 Disease study as compared with placebo and Time 4.4/3.6 mm Hg with trandolopril in the Prevention OD- Once a day dose BD- Twice a day dose of Events with angiotensin-converting Enzyme in- Figure 2 Mean diastolic ABP profile. o.d. – once-a-day dose; b.d. hibition study.15 These studies suggest negligible or – twice-a-day dose. small falls in OBP after treatment of normotensive

Table 4 Ambulatory systolic BP profile at baseline and after ramipril therapy

SBP at baseline SBP twice daily ramipril 5 mg P-valuea SBP once daily ramipril 10 mg P-valueb

12.00–15.00 h 127.3 (15.7) 120.1 (14.4) 0.012 118.6 (12.9) 0.007 01.00–04.00 h 113.1 (16.1) 106.7 (14.0) 0.042 104.6 (11.8) 0.002 05.00–08.00 h 120.5 (14.6) 112.7 (16.6) 0.003 114.5 (12.7) 0.029 Mean 24 h pressure 123.7 (14.7) 116.9 (13.2) o0.001 115.1 (11.1) o0.001 OBP 132.8 (11.1) 129 (17.9) 0.2 131.2 (15.3) 0.49

Abbreviations: OBP, office blood pressure; SBP, systolic blood pressure. aPaired t-test between the baseline and the twice daily dose. bPaired t-test between the baseline and the once daily dose. Data as mean (standard deviation). No statistical difference between the once-daily and twice-daily dose.

Table 5 Ambulatory DBP profile at baseline and after ramipril therapy

DBP at baseline DBP twice daily ramipril 5 mg P-valuea DBP once daily ramipril 10 mg P-valueb

12.00–15.00 h 77.1 (11.2) 73.4 (12.1) 0.033 71.3 (8.9) 0.009 01.00–04.00 h 65.5 (9.7) 60.5 (9.7) 0.019 59.7 (7.4) 0.001 05.00–08.00 h 71.3 (9.6) 66.0 (10.2) 0.001 67.6 (8.6) 0.057 Mean 24 h pressure 73.3 (9.1) 69.3 (9.6) o0.001 68.3 (7.2) o0.001 OBP 80.85 (9.8) 79.11 (11.2) 0.3 77.7 (8.2) 0.15

Abbreviations: DBP, diastolic blood pressure; OBP, office blood pressure. aPaired t-test between the baseline and the twice-daily dose. bPaired t-test between the baseline and the once-daily dose. Data as mean (standard deviation). No statistical difference between the once-daily and twice-daily dose.

Journal of Human Hypertension Assessment of single versus twice daily dosing of ramipril by ABP D Goyal et al 529 Table 6 Effect of ACE (angiotensin-converting enzyme inhibitor) HOPE study criteria and will typically require therapy on office blood pressure in various trials number of other medications to reduce cardiovascular risk. The influence of BP reduction that we Baseline Office BP office BP after treatment observed may play a larger role in risk reduction than other investigators have proposed. HOPE study 139/79 136/77 HOPE substudy 151/81 143/79 This study (o.d. dose) 133/81 131/78 EUROPA study 137/82 128/78 Acknowledgements PEACE study 133/78 129/74 We thank Melaine Kite and Mike Ebanks for their Abbreviations: EUROPA study, European trial on reduction of cardiac help in data collection. We thank Dr Sunil Nadar for events with Perindopril in patients with stable coronary artery disease; PEACE study, Prevention of Events with angiotensin- help with graphs. converting Enzyme inhibition study. patients with a variety of ACE inhibitors. In contrast, References ambulatory recordings suggest more clear cut and 1 The Heart Outcomes Prevention Evaluation Study significant falls in BP as observed in the HOPE Investigators. Effects of an angiotensin-converting- 9 substudy and in our study. One might argue that the enzyme inhibitor, Ramipril on cardiovascular events high baseline OBP in the HOPE substudy would in high risk patients. N Engl J Med 2000; 342: 145–153. favour a greater fall; our patients had OBP lower 2 Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, than in the main HOPE study. Probstfield J, Heart Outcomes Prevention Evalua- The rationale to reduce night time pressure in tion (HOPE) Study. Blood-pressure reduction and high-risk patients for a future cardiovascular event cardiovascular risk in HOPE study. Lancet 2001; 358: is supported by several studies, which suggested 2130–2131. that an increase in night-to-day ratio of BP leads to 3 Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, 16,17 Caulfield M, et al., ASCOT Investigators. Prevention of an increased risk of cardiovascular events. On cardiovascular events with an antihypertensive regi- the other hand, there are studies that raise serious men of amlodipine adding perindopril as required concerns about further reduction of night-time BP versus atenolol adding bendroflumethiazide as re- leading to a possible increase in adverse events quired, in the Anglo-Scandinavian Cardiac Outcomes owing to coronary or cerebral hypoperfusion.18–20 Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a The favourable influence of ramipril treatment multicentre randomised controlled trial. Lancet 2005; observed in HOPE study suggests that this was not 366: 895–906. an important factor in the patients recruited in the 4 Thuillez C, Richer C, Giudicelli JF. Pharmacokinetics, HOPE study. converting enzyme inhibition and peripheral arterial In conclusion, ramipril is effective in lowering BP haemodynamics of ramipril in healthy volunteers. Am J Cardiol 1987; 59: 38D–44D. over a 24-h period when given in either once daily 5 Meyer BH, Muller FO, Badian M, Eckert HG, Hajdu P, in the morning or twice daily regime and assessed Irmisch R et al. Pharmacokinetics of ramipril in the by ABP monitoring. Once-daily treatment is likely to elderly. Am J Cardiol 1987; 59: 33D–37D. aid compliance, especially in patients who fulfil 6 Debusmann ER, Pujadas JO, Lahn W, Irmisch R, Jane F, Kuan TS et al. Influence of renal function on the pharmacokinetics of ramipril (HOE498). Am J Cardiol What is known about the topic? 1987; 59: 70D–78D. K In the HOPE study, use of the ACE inhibitor ramipril in a 7 Schunkert H, Kindler J, Gassmann M, Lahn W, Irmisch dose of 10 mg once daily at night time was associated with R, Debusmann ER et al. Steady-state kinetics of a 22% relative risk reduction in cardiovascular death, ramipril in renal failure. J Cardiovasc Pharmacol myocardial infarction or stroke, despite only a modest 1989; 13: S52–S54. reduction of 3/2 mm Hg in OBP. 8 The AIRE Study Investigators. Effect of Ramipril on K In a subsequent ambulatory substudy of the HOPE study, investigators showed a significant reduction in the night mortality and morbidity of survivors of acute myocar- time ABP but not of the daytime BP when treated with dial infarction with clinical evidence of heart failure. ramipril 10 mg once daily to be given at bedtime. Lancet 1993; 342: 821–828. 9 Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J. What this study adds? Comparative effects of ramipril on ambulatory and K In a similar group of patients as HOPE study, our ABP study office blood pressures. A HOPE substudy. Hyperten- showed a significant reduction of both daytime and night sion 2001; 38: e28–e32. time BP when treated with either ramipril 5 mg twice a day 10 Verdecchia P, Schillaci G, Guerrieri M, Gatteschi C, or ramipril 10 mg once a day given in the morning. Benemio G, Boldrini F et al. Circadian blood pressure K The influence of BP lowering with ramipril observed in our study may have played a larger role in risk reduction than changes and left ventricular hypertrophy in essential other investigators have proposed. hypertension. Circulation 1990; 81: 528–536. 11 Goyal D, MacFadyen RJ, Watson R, Lip GYH. Abbreviations: ABP, ambulatory blood pressure; ACE, angiotensin- Ambulatory blood pressure monitoring in heart failure: converting-enzyme; BP, blood pressure; HOPE, Heart Outcomes a systematic review. Eur J Heart Failure 2005; 7: Prevention Evaluation study; OBP, office blood pressure. 149–156.

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