Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S16-S22, July 2008

24-hour powerful blood pressure-lowering: is there a clinical need?

Based on material presented at a Boehringer Ingelheim-Sponsored Meeting held in Madrid, Spain, May 4–5, 2007.

  • Gordon McInnes, BSc, MD, FRCP

      Affiliations

    • Corresponding Author InformationCorresponding author: Gordon McInnes, BSc, MD, FRCP, Division of Cardiovascular and Medical Sciences, Faculty of Medicine, Western Infirmary, University of Glasgow, Glasgow G11 6NT, United Kingdom. Tel: +44 141 211 2319; fax: +44 141 211 2895.

Division of Cardiovascular and Medical Sciences, Faculty of Medicine, Western Infirmary, University of Glasgow, Glasgow, United Kingdom

Article Outline

Abstract 

Attenuation of 24-hour blood pressure (BP) fluctuation, and control of the early morning BP surge, may help to improve cardiovascular outcomes in hypertensive patients. However, studies show that early morning BP is generally poorly controlled even in patients with well-controlled clinic BP. Few antihypertensives are sufficiently long-acting to sustain adequate BP-lowering for the full 24 hours between once-daily doses, and indeed many are at their lowest efficacy during the risky early morning period. The angiotensin receptor blocker (ARB) telmisartan has the longest plasma half-life, highest lipophilicity, highest receptor binding affinity, and slowest dissociation of any ARB, making it particularly suitable for sustained 24-hour BP control. In clinical studies, telmisartan provides 24-hour BP control superior to that of the ARBs losartan and valsartan, the calcium-channel blocker amlodipine, and the angiotensin-converting enzyme (ACE) inhibitor ramipril. This agent is particularly effective during the last 6 hours of the dosing interval when the other antihypertensives tend to go down in effectiveness. Telmisartan is, therefore, a highly appropriate antihypertensive for sustained 24-hour BP control, especially during the risky early morning hours.

Keywords: Early morning blood pressure surge, telmisartan, smoothness index, blood pressure control

 

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Introduction 

Blood pressure (BP) fluctuates throughout the 24-hour period, with higher levels during the daytime, lower levels at night during sleep, and a characteristic sharp rise in the early morning upon waking (referred to as the early morning BP surge).1, 2 This rhythm is exaggerated in individuals with hypertension. Evidence from cross-sectional3, 4, 5, 6, 7 and longitudinal studies8, 9, 10 shows that the amplitude of BP variation throughout the day correlates with the extent of target-organ damage (e.g., left ventricular hypertrophy, carotid artery atherosclerosis, cerebrovascular damage, and renal damage) in hypertensive patients.

The early morning BP surge appears to be an important trigger for cardiovascular events. Epidemiological data examining the distribution of cardiovascular events throughout the day indicate that cardiovascular complications such as stroke,11 myocardial infarction,12 and coronary ischemia13 occur with the highest frequency in the morning, coincident with the early morning BP surge. Figure 1 illustrates that strokes occurred in awake patients between 10:00 and 12:00 hours more frequently than at any other time period,11 and myocardial infarction was also significantly more frequent between 6:00 and 12:00 hours (P < .01), with a peak incidence around 9:00 hours.12 Prospective studies have also shown an association between the early morning BP surge and an increased risk of cardiovascular events. In one study, 24-hour ambulatory BP monitoring and brain magnetic resonance imaging in elderly hypertensive patients revealed that a greater than median early morning BP surge (>55 mm Hg increase above trough night-time levels of systolic blood pressure [SBP]) was associated with a significantly higher frequency of silent multiple cerebrovascular infarcts at baseline (57% vs. 33%; P < .001) and clinical stroke (19% vs. 7.3%; P < .004) during 41 months of follow-up, compared with patients in whom there was a lesser early morning BP surge.14 In a second study in initially untreated hypertensive individuals, 24-hour ambulatory BP monitoring confirmed that the early morning rise in BP carried an increased risk of cardiovascular complications, independent of age, and mean 24-hour SBP.15

Since the early morning rise in BP is linked with an increased risk of cardiovascular complications, blunting of this BP surge with appropriate antihypertensive treatment should protect against cardiovascular events during the vulnerable early morning hours. Yet prospective studies of 24-hour BP control in hypertensive patients show that early morning BP is generally poorly controlled. In the Analysis of the Control of Blood Pressure using Ambulatory Blood Pressure Monitoring (ACAMPA) Study in Spain16 and the Jichi Morning-Hypertension Research (JMORE) Pilot Study in Japan,17 around half of the hypertensive patients with well-controlled clinic BP (<140/90 mm Hg) had poorly controlled early morning BP (>135/85 mm Hg); in the ACAMPA Study, this proportion rose to 70% among patients with poor clinic BP control.16

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Difficulties in Achieving 24-Hour BP Control 

Many antihypertensive agents used to treat high BP do not provide sustained antihypertensive activity for a full 24 hours. Usually, BP-lowering drugs are taken in the morning at breakfast, with the peak antihypertensive effect occurring around midday. Trough concentrations of antihypertensive agents administered once daily occur the following morning, with most providing little BP-lowering activity during this crucial time period.

The sustainability of a drug's effect over 24 hours can be described by mathematical indices such as the trough-to-peak ratio, which is calculated by dividing the BP reduction at trough by its reduction at peak and multiplying the result by 100%, giving an easily understood index of efficacy over the dosage interval.18 Drugs that provide sustained BP control throughout the dosing interval have trough-to-peak ratios close to 100%. The angiotensin receptor blocker (ARB) telmisartan has a trough-to-peak ratio of around 92% for SBP and 100% for diastolic blood pressure (DBP), indicating BP-lowering effects during the trough period in the morning are similar to those at peak, a few hours after drug administration.19

Although useful, trough-to-peak ratios do not reflect the true homogeneity of BP control throughout the 24-hour dosing interval. The smoothness index (SI) is now considered to be a better indicator of BP homogeneity over time. The SI is calculated by taking the average of hourly changes in BP induced by treatment over 24 hours, and dividing this by the standard deviation. SI values greater than 1 indicate a reliable and homogenous antihypertensive effect over 24 hours.20 The SI is highly reproducible and has been validated in clinical trials where SI shows a strong correlation with 24-hour BP variation and is an independent, clinically relevant, prognostic indicator of target organ damage.20, 21, 22

A recent meta-analysis, which assessed the SI for standard daily doses of drugs from different classes of antihypertensive, showed that telmisartan has an SI higher than that with losartan, valsartan, or ramipril, and equivalent to that with the long-acting antihypertensive amlodipine. In this analysis, the SI for telmisartan 80 mg was 1.13 SBP and 0.97 DBP; losartan 50 mg was found to have the lowest SI (0.66 SBP and 0.57 DBP).21 The SI for telmisartan predicts that this drug will maintain consistent BP-lowering over the full 24 hours between doses, including the risky early morning period immediately prior to the next dose. This prediction is supported by the results from numerous clinical trials. In two independent titration-to-response comparisons of telmisartan 50 to 100 mg vs. losartan 40 to 80 mg each administered once daily in mild-to-moderate hypertension, SBP reduction at the end of the dosage interval in each study was significantly greater (P < .05) with telmisartan than with losartan.23, 24 In the MICADO II study, which enrolled moderately hypertensive patients, telmisartan 80 mg once daily showed powerful SBP reduction throughout the 24-hour dosing interval, particularly during the last 6 hours (coincident with the early morning BP surge), when telmisartan provided significantly greater BP-lowering than valsartan administered at the recommended dose of 160 mg once daily (P = .02).25

Telmisartan also provides greater 24-hour BP control compared with ramipril, the angiotensin-converting enzyme (ACE) inhibitor used in the landmark Heart Outcomes Prevention Evaluation (HOPE) Study.26 In the PRISMA I and II studies (Prospective, Randomized Investigation of the Safety and efficacy of telMisartan vs. ramipril using Ambulatory BP monitoring), in which patients with mild-to-moderate hypertension (95 to 109 mm Hg seated DBP) were randomized to once-daily treatment with telmisartan 80 mg or ramipril 5 mg force-titrated to 10 mg, the reductions in both SBP and DBP during the last 6 hours of the dosing interval were significantly greater with telmisartan 80 mg than with ramipril 10 mg (P < .0001); similar findings were observed throughout the 24-hour dosing period.27, 28 In a pooled analysis of those patients in PRISMA I and II with a high early morning SBP surge (≥37 mm Hg) at baseline, BP-lowering during the early morning hours with telmisartan (−12.7 mm Hg) was significantly greater than with ramipril (−7.8 mm Hg; P < .0004).29

Telmisartan also has a very favorable BP profile compared with amlodipine, a calcium-channel blocker with a long duration of action.30 In a comparison of telmisartan 40 to 120 mg and amlodipine 5 to 10 mg each given once daily, telmisartan provided BP-lowering throughout the 24-hour period at least as effective as amlodipine and produced significantly greater reductions in DBP (P < .05) towards the end of the dosing interval (last 4 hours), when cardio- and cerebrovascular events are most likely to occur.31

Prescribing antihypertensives like telmisartan with a prolonged duration of action not only provides BP-lowering during the vulnerable early morning hours but also mitigates against the loss of BP control if a dose is missed. In a pooled analysis of two studies comparing telmisartan 80 mg with valsartan 160 mg once daily during the 24 hours after a missed dose in patients with mild-to-moderate hypertension (MICADO I and II studies), telmisartan sustained BP control after a missed dose significantly better than with valsartan (P < .05 daytime; P < .001 nighttime), an effect that was particularly marked during the last 6 hours of the dosing interval (P < .0001) (Figure 2).32

  • View full-size image.
  • Figure 2. 

    Changes in SBP control in the 24 hours after a missed dose of telmisartan 80 mg or valsartan 160 mg in patients with mild-to-moderate hypertension (the MICADO I and II studies). SBP, systolic blood pressure. Reproduced with permission from Lacourciere Y, Krzesinski JM, White WB, Davidai G, Schumacher H. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit 2004;9:203–10.32

These comparisons show that at recommended daily doses, telmisartan monotherapy provides early morning BP control significantly better than many ARBs, calcium-channel blockers, and ACE inhibitors. In individuals with hypertension that require combination therapy to achieve adequate BP control, the most logical combination will comprise one drug that controls vasoconstriction plus a second that affects volume overload (e.g., an ARB plus a diuretic; see article by Williams in this supplement). Combination of a relatively short-acting antihypertensive agent, such as losartan, with a longer acting agent such as hydrochlorothiazide (HCTZ) can result in improved magnitude and duration of 24-hour BP reduction. However, prolongation of action is attributable to only one of the constituents. Combining two longer-acting agents would be anticipated to provide a better BP profile over the dosage interval. In a comparison of two fixed-dose combinations of long-acting antihypertensives plus HCTZ in elderly hypertensive individuals (the ATHOS [A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension] Study), telmisartan plus HCTZ gave significantly superior BP control over 24 hours (P < .001), during the daytime (P < .001), and in the early morning (P < .05) compared with amlodipine plus HCTZ (Figure 3).33

  • View full-size image.
  • Figure 3. 

    Changes in 24-hour, daytime, nighttime, and morning SBP following treatment with telmisartan plus HCTZ or amlodipine plus HCTZ (the ATHOS [A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension] Study). HCTZ, hydrochlorothiazide; SBP, systolic blood pressure. Reproduced with permission from Neldam S, Edwards C, ATHOS Study Group. Telmisartan plus HCTZ vs. amlodipine plus HCTZ in older patients with systolic hypertension: results from a large ambulatory blood pressure monitoring study. Am J Geriatr Cardiol 2006;15:151–60.33

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Structure and Pharmacokinetic Differences of the ARBs 

The highly favorable 24-hour BP-lowering profile of telmisartan stems from its unique structure and pharmacokinetic properties. While most ARBs include a characteristic ring structure (a bi-phenyl tetrazole group), telmisartan does not possess this moiety (Figure 4). This structural novelty contributes to the pharmacological properties of telmisartan, including the way in which telmisartan binds to the angiotensin II type 1 (AT1) receptor. Telmisartan has a very high affinity for the AT1 receptor, greater than that of other ARBs, and consequently the dissociation half-life for telmisartan — the length of time taken for the molecule to dissociate from the receptor — is the longest of all the ARBs.34 High affinity for, and slow dissociation from, the AT1 receptor translates into insurmountable inhibition of angiotensin II by telmisartan at the receptor. Whereas surmountable inhibition at the receptor site (as seen with most ARBs) can be overcome by high levels of angiotensin II, insurmountable inhibition means that angiotensin II cannot completely overcome the inhibition while the antagonist is present at the receptor. In angiotensin II activity assays using isolated rabbit aorta, telmisartan induces insurmountable antagonism of angiotensin II-induced contractile activity,35 which is only slowly reversible showing that the drug binds firmly at the AT1 receptor and is difficult to dislodge through competitive inhibition with angiotensin II.

The pharmacokinetic attributes of telmisartan help to further explain the observed long duration of action. Elimination half-life of about 24 hours is greater than those of other ARBs (Figure 5).36, 37 Telmisartan has relatively low protein binding and is highly lipophilic38 resulting in the greatest volume of distribution among drugs of this class.39 Extensive binding of telmisartan within tissues yields a reservoir of drug available for later release into the circulation, a property that enhances the time course of efficacy of telmisartan.

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Conclusions 

BP variability throughout the day, and especially in the early morning, is a key determinant of cardiovascular damage and the likelihood of cardiovascular events in hypertensive individuals. Reducing the amplitude of BP variation throughout the dosing interval and attenuating the spike in early morning BP is, therefore, a logical goal of antihypertensive therapy. However, most of the currently available antihypertensives have a lower plasma half-life, which may be considered crucial in terms of full 24-hour BP-lowering.

In contrast to other agents, telmisartan has an exceptionally long duration of action and in clinical trials provides sustained BP control over the full 24-hour dosing period. Telmisartan has a high affinity for and slow dissociation from the AT1 receptor, resulting in insurmountable angiotensin II antagonism. Telmisartan also has the longest plasma half-life of all the clinically available ARBs, and, together with high volume of distribution, lipophilicity, and tissue penetration; this allows telmisartan to sustain activity over a full 24 hours, giving full BP-lowering effects over the entire dosing interval, including the risky early morning hours. This enhances its appeal to patients and minimizes the potential for noncompliance. Thus, the pharmacological properties of telmisartan make it a highly appropriate ARB to use for controlling BP throughout the 24-hour dosing period, especially during the potentially dangerous early morning BP surge.

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 Conflict of interest: none.

PII: S1933-1711(08)00038-7

doi:10.1016/j.jash.2008.03.004

Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S16-S22, July 2008

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