Eoin O’Brien

Structure-based design of aliskiren, a novel orally effective renin inhibitor

Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.

Ambulatory Arterial Stiffness Index as a Predictor of Cardiovascular Mortality in the Dublin Outcome Study

We hypothesized that the dynamic relation between diastolic and systolic blood pressure over 24 hours provides a measure of arterial stiffness and might, therefore, predict cardiovascular mortality over and above pulse pressure. At baseline, while not on antihypertensive medication, 11 291 patients (mean age, 54.6 years; 5965 women) underwent ambulatory blood pressure monitoring. Using all of the blood pressure readings, we plotted diastolic against systolic blood pressure from each individual and calculated the regression slope. The ambulatory arterial stiffness index (AASI) was defined as 1 minus this regression slope. Over a median follow-up of 5.3 years, 566 cardiovascular deaths occurred, including 151 from stroke and 358 from cardiac disorders. Before and after adjustment for other cardiovascular risk factors, AASI and pulse pressure significantly predicted total cardiovascular mortality. AASI was a stronger predictor than pulse pressure for stroke (mutually adjusted relative hazard ratios for 1 SD increase, 1.21 versus 1.04; P=0.02 versus 0.66) with the opposite trend for cardiac mortality (relative hazard ratios, 1.03 versus 1.21; P=0.63 versus 0.002). In subjects with normal daytime ambulatory blood pressure (<135/<85 mm Hg), AASI was more predictive than pulse pressure of cardiovascular mortality (1.26 versus 0.96; P=0.04 versus 0.70) and of stroke mortality (1.81 versus 1.12; P=0.007 versus 0.58), whereas neither independently predicted cardiac mortality (1.11 versus 0.89; P=0.47 versus 0.40). AASI is a novel measure of arterial stiffness, which can be readily determined from ambulatory blood pressure recordings and which independently predicts cardiovascular mortality, even in normotensive subjects.

Response to Antihypertensive Therapy in Older Patients With Sustained and Nonsustained Systolic Hypertension

BackgroundThe goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension. Methods and ResultsPatients who were ≥60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (≥160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (P <0.001) and, during follow-up, a lower incidence of stroke (P <0.05) and of cardiovascular complications (P =0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (P <0.001). The influence of active treatment on ECG voltages (P <0.05) and on the incidence of stroke (P <0.05) and cardiovascular events (P =0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension. ConclusionsPatients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n=23), ramipril (n=21), or irbesartan (n=23). In the diuretic combination study, the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure, compared with aliskiren monotherapy (systolic/diastolic mean change from baseline [SEM]: daytime: −18.4 [2.1]/ −10.6 [1.7] versus −10.4 [1.8]/−5.8 [1.4]; nighttime: −15.6 [2.7]/−8.1 [1.8] versus −8.8 [2.9]/−5.0 [2.2]). In the angiotensin-converting enzyme inhibitor combination study, the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy (daytime: −10.5 [2.9]/−8.1 [2.1] and −14 [3.7]/−8.7 [2.3] versus −6.1 [2.4]/−5.9 [1.5]; nighttime: −8.1 [2.6]/−5.3 [2.4] and −9.6 [3.4]/−5.3 [2.4] versus −2 [2.3]/−0.7 [2.2]). In the angiotensin receptor blocker combination study, the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone, for 3 weeks, resulted in significantly lower nighttime pressures compared with irbesartan monotherapy (daytime: −14.8 [2]/−8.2 [1.3] and −13.3 [1.6]/−6.8 [0.9] versus −11.4 [1.6]/−6.5 [1.1]; nighttime: −16.1 [2.4]/−8.6 [1.7] and −13.2 [2.7]/−7.2 [1.9] versus −9.0 [2.5]/−4.7 [1.9]). Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (P<0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased (combination therapy versus untreated; median [interquartile range]; aliskiren and hydrochlorothiazide: 0.4 [0.2 to 1.1] versus 0.7 [0.5 to 1.3]; ramipril and aliskiren: 0.5 [0.3 to 0.9] versus 0.6 [0.5 to 0.8]; irbesartan and aliskiren: 0.4 [0.2 to 0.9] versus 0.6 [0.4 to 0.9]). These results suggest that renin inhibition with aliskiren in these combinations increases renin-angiotensin system suppression, improves 24-hour blood pressure control, and may ultimately provide better end-organ protection in patients with hypertension.

State of the Market: A Review of Ambulatory Blood Pressure Monitoring Devices

The introduction of 24-hour ambulatory blood pressure measurement into clinical practice created a large market for ambulatory blood pressure measurement devices. Forty-three such devices from 31 manufacturers or suppliers are now available to satisfy a market demand that is likely to increase. The aim of this article is to identify the devices available and then to examine critically any validation studies assessing accuracy and performance. Of the 43 devices available 18 have been validated according to the protocols of the Association for the Advancement of Medical Instrumentation (AAMI) or the British Hypertension Society (BHS) in 25 reported studies. In 9 of these studies the protocol was not adhered to, and the results, which are therefore questionable, are noted but not considered further. Fourteen devices were evaluated according to the accuracy criteria of both protocols, and of these 9 fulfilled the requirements. From this review of 43 devices on the market it may be concluded that, at the time of writing, there is published evidence for only 9 devices meeting the generally accepted AAMI and BHS criteria for accuracy and performance; these are the A&D TM-2420 models 6 and 7 and TM-2421, CH-Druck, Nissei ABPM DS-240, Profilomat, QuietTrak, and SpaceLabs SL-90202 and SL-90207.

Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: Objectives, protocol, and organization

SummaryThe Syst-Eur Trial is a concerted action of the European Community’s Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood. Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure.To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160–219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10–40 mg/day), combined with enalapril (5–20 mg/day) and hydrochlorothiazide (12.5–25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and perprotocol comparison of the outcome in the 2 treatment groups.A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).

When Can the Practicing Physician Suspect White Coat Hypertension? Statement From the Working Group on Blood Pressure Monitoring of the European Society of Hypertension

T he Centers for Medicare and Medicaid Services (CMS) in the United States have recently approved ambulatory blood pressure measurement (ABPM) for reimbursement, but only for “patients with suspected WCH (white coat hypertension)” in whom the CMS believes the information deriving from the technique “is necessary in order to determine the appropriate management of the patient.” This decision, which is likely to change the clinical management of hypertension in the United States, makes white coat hypertension a condition of major importance. The decision by the CMS begs the question as to how the practicing physician can select patients with white coat hypertension. It might indeed be argued that all patients with an elevated clinic blood pressure (BP) are candidates for ABPM. However, the CMS decision carries a few other stipulations. First, white coat hypertension should be defined as “office BP 140/90 mm Hg on at least three separate clinic/office visits with two separate measurements made at each visit.” Second, in addition “there should be at least two BP measurements taken outside the office which are 140/90 mm Hg.” Third, “there should be no evidence of endorgan damage.” Fourth and last, patients selected for ABPM on the foregoing criteria who have” an ambulatory BP 135/85 (presumably average daytime pressure, although this is not stated) with no evidence of end-organ damage” are likely to be at normal risk, whereas those patients whose pressures are above this level “may be at increased cardiovascular risk, and a physician may wish to consider antihypertensive therapies.” In anticipation of a considerable increase in the use of ABPM in clinical practice in the United States, it is timely to examine the CMS recommendations in the light of recent evidence from a number of studies on WCH.

Prognostic Effect of the Nocturnal Blood Pressure Fall in Hypertensive Patients: The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) Meta-Analysis.

The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment ( P <0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels. # Novelty and Significance {#article-title-42}The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment (P<0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels.

Ambulatory Blood Pressure Measurement: What Is the International Consensus?

The Working Group on Blood Pressure Monitoring of the European Society of Hypertension (ESH) published recommendations for blood pressure (BP) measurement in 20031 and a guideline for home BP measurement in 2008.2 Ambulatory BP monitoring (ABPM) has become a subject of considerable scientific interest with >10 000 articles listed on PubMed in 2012. In 2001, the Center for Medicare and Medicaid Services in the United States approved ABPM for reimbursement for the identification of subjects with white-coat hypertension,3 and in 2011, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom recommended that ABPM should be offered as a cost-effective technique to all people suspected of having hypertension.4 One of the first meetings to examine the potential of ABPM was held in Ghent in 1978,5 and since then the ESH Working Group on Blood Pressure Monitoring has held several consensus conferences, the most recent being in Milan in 2011. The technique was comprehensively reviewed and, arising from this meeting, a position article was drafted incorporating the opinions of 34 international experts in hypertension and BP measurement.6 During the drafting of this article, it became apparent, first, that the large literature on ABPM was in need of assessment but that drafting a systematic review on this topic would be a difficult task, given the very large number of studies dealing with ABPM, and second, that even among experts, there was differing opinion on certain basic aspects of ABPM, such as the definition of white-coat and masked hypertension. In this article, we highlight these areas of potential controversy, not as an indictment of expert opinion but rather to illuminate aspects of the technique in need of clarification, and perhaps, as importantly, in need of further research. Most devices available for ABPM have been validated …

Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white-coat and masked hypertension in the population

Outcome-driven recommendations about time intervals during which ambulatory blood pressure should be measured to diagnose white-coat or masked hypertension are lacking. We cross-classified 8237 untreated participants (mean age, 50.7 years; 48.4% women) enrolled in 12 population studies, using ≥140/≥90, ≥130/≥80, ≥135/≥85, and ≥120/≥70 mm Hg as hypertension thresholds for conventional, 24-hour, daytime, and nighttime blood pressure. White-coat hypertension was hypertension on conventional measurement with ambulatory normotension, the opposite condition being masked hypertension. Intervals used for classification of participants were daytime, nighttime, and 24 hours, first considered separately, and next combined as 24 hours plus daytime or plus nighttime, or plus both. Depending on time intervals chosen, white-coat and masked hypertension frequencies ranged from 6.3% to 12.5% and from 9.7% to 19.6%, respectively. During 91 046 person-years, 729 participants experienced a cardiovascular event. In multivariable analyses with normotension during all intervals of the day as reference, hazard ratios associated with white-coat hypertension progressively weakened considering daytime only (1.38; P=0.033), nighttime only (1.43; P=0.0074), 24 hours only (1.21; P=0.20), 24 hours plus daytime (1.24; P=0.18), 24 hours plus nighttime (1.15; P=0.39), and 24 hours plus daytime and nighttime (1.16; P=0.41). The hazard ratios comparing masked hypertension with normotension were all significant (P<0.0001), ranging from 1.76 to 2.03. In conclusion, identification of truly low-risk white-coat hypertension requires setting thresholds simultaneously to 24 hours, daytime, and nighttime blood pressure. Although any time interval suffices to diagnose masked hypertension, as proposed in current guidelines, full 24-hour recordings remain standard in clinical practice.