Antihypertensive drug therapy plays a crucial role in reducing cardiovascular morbidity and mortality in patients with elevated blood pressure. Although clear and robust benefits in stroke reduction have been evidenced, the effects of blood pressure control on reducing coronary risk is less clear. In the last 15 years, considerable attention has focused on improving existing treatments with the hope of achieving more clearly defined benefits in preventing the coronary sequelae of hypertension 1,2.
Two key areas are the development of antihypertensive therapies that enhance compliance through once-daily dosing and reduce blood pressure consistently and smoothly throughout the dosing interval. In conjunction with these developments are changes in how drug therapy is assessed in clinical trials. Conventional evaluation techniques have focused on assessing blood pressure at single points in time, usually through effects performed in an office or clinic. These are now supplemented by newer techniques, such as ambulatory blood pressure monitoring that continuously monitor changes in blood pressure during the routine activities of daily living. These newer techniques provide the tools for more detailed and accurate assessments of the effects of antihypertensive medications.
Using ambulatory blood pressure monitoring, significant differences have been uncovered in how once-daily medications affect blood pressure over the entire 24-h dosing interval. Although many clinicians believe that once-daily medications provide 24-h protection, differences in trough : peak ratios and other pharmacodynamic parameters often reveal less consistent and durable effects. The purpose of this article is to review the significance of 24-h control in maintaining normal circadian blood pressure patterns and its relation to target-organ complications. Older and newer antihypertensive agents will be discussed in relation to newer criteria for assessing the 24-h efficacy of these drugs.
Normal blood pressure patterns and their clinical significance
Blood pressure in normotensive individuals who follow a typical sleep–wake cycle (awake during the day and asleep at night) exhibits a characteristic circadian pattern, exemplified by a sharp increase during the early morning hours (upon awakening) that reaches a plateau around 1100 h. After this, the blood pressure level gradually declines, reaching its lowest value around 2400 h 3,4. Such changes in blood pressure are believed to be related to underlying changes in sympathetic nervous system activity that parallel the normal sleep–wakecycle. The circadian pattern of blood pressure typical in normotensive individuals is also seen in most untreated patients with hypertension, although in the latter case the pattern is shifted upward 5. Despite treatment, many patients with hypertension are also seen to have inadequately controlled blood pressure on ambulatory blood pressure monitoring, particularly during the vulnerable early morning period.
The morning surge in blood pressure is significant in light of pathophysiologic and epidemiologic studies that have characterized a morning increase in the frequency of sudden cardiac death 6 and acute myocardial infarction 7, among other cardiovascular sequelae. One major drawback of blood pressure assessments that rely on isolated readings, generally taken in an office or clinic setting, is that they are not designed to show whether a given treatment is adequately controlling blood pressure during this period of high vulnerability 3.
The association between elevated blood pressure and cardiovascular disease was established using conventional recordings and they remain the most readily available and cost-effective means of measuring blood pressure. However, a number of additional weaknesses are associated with conventional blood pressure monitoring in an office setting. For example, clinic blood pressure recordings are generally higher than those recorded with ambulatory blood pressure monitoring and provide a relatively poor correlation with mean blood pressure over 24 h 8. This finding has been attributed to the well-known phenomenon of ‘white-coat’ hypertension, in which certain subjects exhibit higher clinic pressures, possibly related either to the anxiety associated with visiting a doctor's office or to an alerting response to having their blood pressure measured manually 8,9. Despite high clinic blood pressure values, patients with white-coat hypertension appear to have a risk of cardiovascular disease similar to that of subjects with normal blood pressure on office recordings 10. Furthermore, conventional blood pressure recordings generally cannot differentiate between white-coat hypertension and persistent hypertension, which confers a significantly increased risk of cardiovascular morbidity and mortality.
Conventional office readings can also introduce a certain amount of time and observer bias. Consequently, assessing blood pressure at a single point in time provides only a limited, discrete view of an antihypertensive agent's hemodynamic and metabolic effect 4. In contrast, ambulatory blood pressure monitoring typically includes more than 50 recordings over a single 24-h period 11, which greatly improves the validity of mean 24-h blood pressure levels and the potential to detect even small differences among therapies. Finally, there is a poor correlation between conventional blood pressure recordings and left ventricular mass 10. Although the cost of ambulatory blood pressure monitoring is prohibitive for routine use, it is of particular benefit to clinicians in diagnosing white-coat hypertension and evaluating resistant hypertension 11. Its primary value, however, remains as a research tool.
The importance of 24-h blood pressure monitoring in evaluating antihypertensive efficacy and variations in blood pressure profiles
Therapies aimed at reducing the cardiovascular morbidity and mortality of hypertension should provide effective blood pressure reduction during the full 24-h dosing interval. Ambulatory blood pressure monitoring provides one noninvasive method of assessing the ability of agents to achieve this goal 12,13. Modern ambulatory blood pressure monitoring cuff devices are small, quiet, and lightweight in order to remain as unobtrusive as possible, with the least possible disturbance to the patient. Devices can measure blood pressure either by auscultatory or oscillometric methods. In the former case, devices may also include chest leads to obtain electrocardiographic R-wave gating that can be matched to the Korotkoff sounds and thereby reduce the chance of noise artifact in the recording. In contrast, the oscillometric method determines fluctuations with the brachial artery through direct palpation of the arm 3,12. Ambulatory cuff monitors typically measure blood pressure every 15 min over 24 h, although the interval between measurements can be increased at night to minimize sleep disturbances. Data are stored in a solid-state memory system for later retrieval 14.
The reproducibility and validity of noninvasive ambulatory blood pressure monitoring has been verified in a number of studies 15,16. Overall, the value of this method of determining blood pressure resides in its ability to define accurately whole-day blood pressure, including circadian fluctuations and differences between daytime and nighttime blood pressure values—important considerations when evaluating the efficacy of antihypertensive agents. Studies using conventional blood pressure measuring techniques generally record morning trough blood pressure levels (24 ± 1.5 h) as a marker for 24-h antihypertensive efficacy. Ambulatory blood pressure monitoring records trough blood pressure levels (24 h) and blood pressure levels throughout the vulnerable early morning period. Although most of the large, multicenter studies evaluating the cardiovascular outcomes related to antihypertensive treatment have employed conventional blood pressure measuring techniques, the use of ambulatory blood pressure monitoring is increasing in newer drug therapy trials. Ambulatory blood pressure monitoring techniques substantially reduce the risk of measuring a placebo effect, since patients without true persistent hypertension can be excluded during diagnostic procedures undertaken at study entry 3.
Ambulatory blood pressure monitoring can also provide more flexibility in the design of trials evaluating the effects of antihypertensive regimens, as fewer patients and possibly less time may be required to detect statistically valid differences between placebo and active drug or between two or more active therapies 17,18. Consequently, the value of this method over conventional blood pressure determinations in clinical trials is considered by most researchers to be indisputable. The discriminatory power of ambulatory blood pressure monitoring may be particularly useful in the study of mildly hypertensive patients in whom even small reductions in blood pressure may be clinically significant 8.
Ambulatory blood pressure monitoring has uncovered important differences in the 24-h blood pressure profiles among hypertensive patients that may allow for potentially more detailed and accurate risk stratification. In a study by Devereux and colleagues 19, ambulatory blood pressure monitoring allowed for more accurate characterization of blood pressure during recurring stress and its relationship to left ventricular hypertrophy in patients with mild hypertension. Blood pressure measured in the clinic was not as closely correlated with left ventricular hypertrophy as blood pressure recorded on weekdays, at work, and under recurring stress.
Ambulatory blood pressure monitoring has also identified a cohort of individuals, termed ‘nondippers’, who exhibit a blunted fall in nocturnal blood pressure. This characteristic has been identified in subgroups, particularly blacks, with both normal and elevated blood pressure and in patients with some types of secondary hypertension 20–22. This altered circadian pattern has been associated with higher cardiovascular risk. In one study, black hypertensive patients showed a smaller mean nocturnal dip and higher mean left ventricular mass than white patients, despite similar mean 24-h blood pressure. Left ventricular mass index was closely correlated with both mean daytime and nocturnal blood pressure in blacks, but only with mean daytime blood pressure in whites with hypertension 23.
Similarly, the diurnal rhythm of blood pressure fluctuations in diabetic patients with hypertension and nephropathy seems to influence target-organ dysfunction 24. Nondippers in a small, retrospective study were found to have a significantly greater rate of decline in renal function compared with a matched group of patients with more normal diurnal blood pressure variations. In another study, nondippers had a significantly higher cardiovascular event rate (4.99) compared with either hypertensive patients with typical circadian blood pressure patterns (1.79) or patients with white-coat hypertension (0.49)20.
The clinical significance of altered circadian patterns in blood pressure have been correlated to increases in blood pressure load and blood pressure variability. Blood pressure load refers to the contribution to cardiovascular risk of both magnitudes of blood pressure elevation and its duration 25. Thus, patients with blunted nocturnal dips in blood pressure are believed to be at increased risk because of deleterious effects of persistently elevated blood pressure and therefore greater blood pressure load on the heart and vasculature 10. Abnormalities in blood pressure variability as assessed by 24-h ambulatory blood pressure measurement have also been independently correlated with poorer outcomes in target-organ function 26. In one study of patients with mild-to-severe essential hypertension, those with high 24-h blood pressure variability had a higher prevalence of target-organ disease than those with low blood pressure variability 26.
The strong correlation between ambulatory blood pressure monitoring and indices of target-organ damage highlights the clinical usefulness of this method of determining blood pressure. Extrapolating from these data, it also appears logical that antihypertensive agents that reduce blood pressure load while maintaining or restoring normal circadian patterns of blood pressure offer the greatest possibility of reducing the cardiovascular complications of hypertension. Furthermore, the ideal antihypertensive agent should provide drug effects that are smooth and consistent over 24 h to reduce blood pressure variability 27.
Role of trough : peak ratios and 24-h monitoring
With the introduction of a number of once-daily antihypertensive medications, many clinicians have assumed that such dosing regimens fully cover a patient for 24 h. However, a careful examination of the differing pharmacodynamic profiles of various agents highlights the continued need for careful assessment. One technique to evaluate the consistency and smoothness of the blood pressure response to antihypertensive drug therapy involves calculating the trough : peak ratio of the drug (Fig. 1)25. This ratio describes the difference between a drug's effect at the end of the dosing interval (trough) and at the time of maximal effects (peak), usually seen a few hours after dosing 25,28. It is customary in clinical trials to calculate the placebo-corrected trough : peak ratio by subtracting the trough : peak ratio of placebo-treated patients from that of the active-treatment group.
Trough : peak ratios that approach a value of 1 are more likely to represent a smooth and consistent reduction in blood pressure 28. In the USA, the Food and Drug Administration (FDA) has set standards for antihypertensive drugs in terms of trough : peak effects. Since it is presumed that most of a drug's effects at peak should still be apparent at trough, the FDA has issued draft guidelines indicating that the trough : peak ratio should not be ≤0.5 29. Others have proposed a more stringent goal of >0.60 5. As shown in Fig. 227, the limitations of clinic blood pressure recordings are easily illustrated when drugs with widely different trough : peak ratios are evaluated with ambulatory blood pressure monitoring. Blood pressure measurements taken during routine office hours (box in Fig. 2) would likely show little difference between two representative agents, one with a trough : peak ratio of 0.45 and the other with a ratio of 0.75 27. However, ambulatory blood pressure monitoring results clearly show a marked difference in each drug's ability to provide smooth and consistent reductions in blood pressure. In particular, the agent with a ratio of 0.45 would probably provide inadequate blood pressure control during the final 4–6 h of the dosing interval. Since most once-daily agents are taken in the morning, the trough period corresponds to that period when the risk of cardiovascular events is highest 27. Furthermore, although increasing the dosage of a drug with a relatively small trough : peak ratio may improve blood pressure control at trough, peak effects may become excessive and place the patient at risk for a hypotensive response or other dose-related adverse effects 3
Discriminating among once-daily antihypertensives using 24-h monitoring
Many benefits have been attributed to treatment with once-daily antihypertensive agents. For example, a single daily dose appears to improve compliance with the antihypertensive regimen 30. However, this appears to translate into clinically meaningful effects only when the duration of the drug's hemodynamic actions extend beyond 24 h. Agents with intrinsically long duration of action may provide additional protection for patients who are poorly compliant 5. Other postulated benefits include decreased blood pressure variability and smoother blood pressure control. Also, long-acting agents that help maintain a normal circadian pattern of blood pressure by providing good coverage during the night may have the added advantage of normalizing circadian patterns in typical nondippers 10.
Despite these potential benefits, a once-daily agent that does not provide 24-h efficacy will fail to control the early morning surge in blood pressure. In a study conducted in our laboratory 31, once-daily treatment with either atenolol (50–100 mg), a beta blocker with a plasma half-life of 6–9 h, or bisoprolol (10–20 mg), a β-blocker with a plasma half-life of 9–12 h, provided similar reductions in office blood pressure measurements. However, when the drugs were compared using 24-h ambulatory blood pressure monitoring, bisoprolol was shown to reduce whole-day diastolic blood pressure by 33% more than atenolol 31. Importantly, bisoprolol also maintained significantly greater blood pressure control during the final 4 h of the dosing interval compared with atenolol (Fig. 3)31. In a study comparing once-daily administration of atenolol and acebutolol, the trough : peak ratio of the former agent was calculated as 0.46 and that of the latter as 0.71 32. Not surprisingly, acebutolol was shown to provide more consistent and durable blood pressure control over the entire dosing interval, including the early-to-midmorning hours 32
Likewise, in a comparison of once-daily treatment with the calcium channel blocker amlodipine (≤10 mg) and the angiotensin-converting enzyme (ACE) inhibitor lisinopril (≤20 mg), ambulatory blood pressure monitoring revealed significant differences between the treatments (Fig. 4)33. Amlodipine provided more consistent control of blood pressure over the entire 24-h dosing period. In particular, blood pressure control appeared compromised with lisinopril during the early morning hours when plasma drug levels were lowest. Comparisons between amlodipine and another calcium channel blocker, felodipine, and the ACE inhibitor ramipril also showed smoother 24-h effects with amlodipine 34,35. These findings are consistent with the trough : peak ratio of amlodipine, which has been estimated at approximately 0.75. In contrast, many other commonly prescribed once-daily antihypertensive agents appear to have trough : peak ratios below the minimally accepted standard of 0.5 10
Angiotensin II receptor blockers (ARBs) and 24-h blood pressure control
Most ambulatory blood pressure monitoring research has focused on newer agents, as noted above, including long-acting calcium channel blockers, ACE inhibitors, and newer β-blockers. Fewer data are available on the 24-h effects of thiazide diuretics and older β-blockers. A growing body of evidence is more clearly defining the 24-h blood pressure effects of ARBs, the newest class of antihypertensives.
Similar to ACE inhibitors, ARBs inhibit the action of angiotensin II, a potent vasoconstrictor that plays a key role in regulating blood pressure 36. Through their effects on aldosterone, as well as direct actions on renal tubules, ARBs also reduce sodium and water retention. ARBs, unlike ACE inhibitors, provide a more specific blockade of angiotensin II because of their more distal actions at the angiotensin type 1 (AT 1 ) receptor.
The specific blockade also results in a more selective inhibition of the renin-angiotensin cascade than that provided by ACE inhibitors 36. Consequently, ARBs as a class are essentially devoid of adverse effects common with nonspecific inhibition of ACE inhibitors, which can lead to the accumulation of polypeptides such as bradykinin and substance P 1. Elevated bradykinin levels have been implicated in the high rate of cough with ACE inhibitors, noted to occur in 5–20% of treated patients 37.
The currently available ARBs are all specific blockers at the AT 1 receptor, including the prototype agent losartan and newer agents such as valsartan, irbesartan, telmisartan candesartan and eprosartan. The efficacy of the ARBs is equivalent to that of ACE inhibitors, calcium channel blockers and β-blockers. Studies comparing eprosartan to enalapril 38, valsartan to amlodipine 39, and irbesartan to atenolol 40 have found them comparable. The addition of hydrochlorothiazide to ARBs significantly enhances their efficacy 41–43.
Studies using ambulatory blood pressure monitoring have generally demonstrated a smooth and consistent effect of newer ARBs on 24-h blood pressure control 44–46. For example, valsartan 80 mg/day controls blood pressure over 24 h and preserves the circadian pattern of blood pressure similar to that seen at baseline but shifted into the normotensive range (Fig. 5)44. These findings are consistent with the calculated trough : peak ratio of 0.69 with valsartan 80 mg, which increases to 0.79 with the 160 mg dose 47. Similarly, other ARBs have trough : peak ratios ≥0.67, the upper number in the FDA guidelines, except for losartan 50 mg which may require twice-a-day dosing 28,47,48
In addition to providing effective reductions in blood pressure with a placebo-like side-effect profile 49, ARBs may have additional benefits on target-organ protection, mainly by reduction of the growth-promoting effects of angiotensin II. Data from clinical studies have demonstrated ARBs to be effective in regression of left ventricular hypertrophy 50,51. Two large, prospective multicenter trials are examining the cardiovascular benefits of ARBs in high-risk hypertensive populations. The Losartan Intervention for Endpoint Reduction (LIFE) trial compares losartan with atenolol in hypertensive patients with electrocardiographically documented left ventricular hypertrophy 52. The Valsartan Antihypertensive Longterm Use Evaluation [VALUE] trial compares valsartan with amlodipine in hypertensive patients, aged 50 years or older, with additional cardiovascular risk or disease factors 53.
To achieve the goal of maximal reduction in target-organ damage, drugs that treat hypertension should effectively lower blood pressure in a smooth, gradual, and sustained manner. Agents with once-daily dosing are preferred to enhance patient compliance. However, care should be taken to choose those once-daily therapies that provide coverage throughout the full 24-h dosing period, as evidenced by adequate trough : peak ratios and supportive ambulatory blood pressure monitoring data. This is particularly important to ensure adequate reduction of total blood pressure load and adequate coverage during the vulnerable early morning hours (typically the last 4–6 h of the dosing interval). Ambulatory blood pressure monitoring has demonstrated crucial differences in the ability of once-daily therapies to achieve these goals. The newer ARBs fulfil these requirements providing sustained blood pressure reductions over 24 h and exhibiting excellent tolerability, characteristics that enhance their use in the clinical setting.
1 Ref 36 Please clarify volume number. Is this only given by month, not number?
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