Interpreting treatment-induced blood pressure reductions ... - Nature

Journal of Human Hypertension (2013) 27, 715–720 & 2013 Macmillan Publishers Limited All rights reserved 0950-9240/13 www.nature.com/jhh

REVIEW

Interpreting treatment-induced blood pressure reductions measured by ambulatory blood pressure monitoring RE Schmieder1, LM Ruilope2, C Ott1, F Mahfoud3 and M Bo¨hm3 It is well known that 24-h ambulatory blood pressure monitoring (ABPM) provides a more accurate picture of a patient’s blood pressure (BP) compared with clinic BP measurement. Twenty-four-hour ABPM better predicts hypertension-related risks such as end-organ damage including left ventricular hypertrophy, cardiovascular (CV) events and mortality. Threshold BP values for hypertension based on 24-h ABPM results have been established, including daytime and night-time averages. Nevertheless, the relationship between 24-h ABPM and clinic BP measurement in patients on antihypertensive therapy, and in particular how each may change in response to antihypertensive therapy, is less clear. This review will provide an overview of current knowledge on the relation between clinic BP and ambulatory BP reductions in clinical trials on antihypertensive therapies. Reduction in CV risk and its correlation with the magnitude of reduction in both clinic and ambulatory BP are explored. The most striking result is that reduction in clinic BP and ambulatory BP do not correspond in a 1:1 fashion, that is, smaller changes in 24-h ABPM correspond to significantly larger changes in clinic BP. Journal of Human Hypertension (2013) 27, 715–720; doi:10.1038/jhh.2013.39; published online 2 May 2013 Keywords: antihypertensive therapy; ambulatory blood pressure; clinic blood pressure

INTRODUCTION Hypertension is a major risk factor for cardiovascular (CV) disease, and measurement of blood pressure (BP) is a fundamental aspect of managing patients with hypertension. It is well known that clinic BP measurements provide an incomplete picture of a patient’s average BP. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is superior to clinic BP measurement for predicting CV events, renal outcomes and mortality.1–3 In addition, 24-h ABPM is superior for prediction of hypertension-related target organ damage, such as left ventricular hypertrophy.4 For this reason, ABPM has been increasingly recommended in the diagnosis and management of hypertension as already suggested in 1999.5 Most recently, the 2011 update of the NIH and Clinical Excellence Guidance on the Management of Hypertension, recommends using ABPM to confirm the diagnosis of hypertension when clinic BP is 4140/90 mm Hg.6 Unlike clinic BP, 24-h ABPM can detect BP fluctuations at different times of the day, such as a nondipping pattern at night, which is associated with increased CV risk.2 Indeed, 24-h ABPM is the only way to determine night-time BP, which is the BP measurement that is the most closely related to CV outcome. Average BP values, as measured by ABPM are generally lower compared with clinic BP values, and the accepted values for diagnosis of hypertension by each method reflect this. In general, clinic BP is considered o140/90 mm Hg, while the threshold o125–130/80 mm Hg is used for BP when measuring by ABPM.7 Importantly, patients benefit (that is, achieve a reduction in CV risk) from reduction in BP, even if they do not achieve BP control below the established threshold for hypertension. As BP reduction is usually discussed in terms of clinic BP, the following question arises: is it a must that reductions in 24-h ambulatory BP be similar

to reductions in clinic BP, in order to achieve the same level of CV benefit? In other words, does a 20 mm Hg reduction in 24-h ambulatory BP have the same implications for CV risk as a 20 mm Hg reduction in clinic BP? The interpretation of 24-h ABPM and the relationship between changes in clinic BP and ambulatory BP will be explored, with a focus on the magnitude of BP reduction that must be achieved by each method in order to achieve a similar benefit in terms of CV risk. This review often refers to treatment-resistant hypertension because under these conditions any discrepancies between ambulatory and clinic BP may be most easily detectable. NORMAL VALUES OF ABPM Mean 24-h ambulatory BP is expected to be several millimeters of mercury (mm Hg) lower than clinic BP. The European Society of Hypertension and European Society of Cardiology have established thresholds for the definition of hypertension using different types of BP measurement. Using 24-h ABPM, the threshold value for hypertension is 125–130/80 mm Hg.7 According to the European Society of Hypertension/European Society of Cardiology guidelines the threshold of daytime ambulatory BP average is 130–135/85 mm Hg, while the threshold night-time average is 120/70 mm Hg.7 Although national and international guidelines provide threshold ambulatory BP values for hypertension, threshold values for severity of hypertension are far less well established. In order to improve the understanding of how ambulatory BP values correlate to clinic BP thresholds for hypertension grades 1–3, Head et al.8 showed by correlating clinic and ambulatory BP that the closer the patient’s BP is to normal levels, the closer is the agreement

1 Department of Nephrology and Hypertension, University Hospital, University Erlangen/Nuremberg, Erlangen, Germany; 2Complutense University, Hypertension Unit, Madrid, Spain and 3Kardiologie, Angiologie, und Internistische Intensivmedizin, Universita¨tsklinikum des Saarlandes, Saarland, Germany. Correspondence: Professor RE Schmieder, Department of Nephrology and Hypertension, University Hospital, University Erlangen/Nuremberg, Ulmenweg 18, Erlangen 91054 Germany. E-mail: [email protected] Received 28 January 2013; revised 19 March 2013; accepted 26 March 2013; published online 2 May 2013

Interpreting BP reductions measured by ABPM RE Schmieder et al

716 Spanish registry study, 37.5% of patients with presumed treatment-resistant hypertension based on clinic BP values were found to be pseudo-resistant when BP was measured by 24-h ABPM.12 Among individuals with diabetes, who had hypertension, the prevalence of pseudo-resistant hypertension was 33%.13 While the clinical significance of white-coat effect is still under discussion, it may be associated with a greater risk of long-term cardiac damage, such as left ventricular hypertrophy.14–16 Identification of white-coat effect in treated patients is important because it can avoid overtreatment with antihypertensive agents associated with side effects. Other patients on antihypertensive therapy exhibit maskedhypertensive effect, that is, BP is apparently controlled based at office visits but is elevated at other times of day. The prevalence of masked-hypertensive effects varies among studies but was recently estimated at 33% of hypertensive patients, who appeared controlled after intensifying their therapy based on clinic BP readings.17 Masked-hypertensive effect is associated with target organ damage, as well as increased CV morbidity and mortality18–21 and is more frequently observed in patients with chronic kidney disase.22 It appears to be prudent to identify and treat patients with this condition, but definitive proof that treating masked hypertension improves prognosis remains to be shown. Neither pseudo-resistant nor masked-hypertensive effect can be diagnosed based on clinic BP alone. Rather, out-of-office BP monitoring techniques are required to identify these conditions. ABPM provides the most complete BP information, including daytime and night-time averages, as well as BP fluctuations, all of which can be clinically important.

between ambulatory BP and clinic BP. At higher BP levels, a greater difference between ambulatory and clinic BP values is observed. Thus, while the clinic BP threshold for grade 1 hypertension, 4140/90 mm Hg, correlated with an ambulatory BP of 133/84 mm Hg, which is a difference of 7/6 mm Hg, grade 2 hypertension (clinic BP 4160/100 mm Hg) correlated with an ambulatory BP of 148/93 mm Hg, a difference of 12/7 mm Hg, and grade 3 hypertension (clinic BP 4180/110 mm Hg) correlated with an ambulatory BP of 163/101 mm Hg, a difference of 17/9 mm Hg. A pattern of increasing discrepancy at more severe grades of hypertension was also observed when daytime and night-time BP were compared with clinic BP, similar to the pattern for 24-h BP (Table 1). A BP measurement of 130/80 mm Hg is well established as an appropriate threshold value for hypertension based on 24-h ABPM. Notably, this threshold value is based only on population studies and meta-analyses. Although many studies have been performed, in which patients were stratified by clinic BP,9–11 not a single prospective long-term study has been conducted in which patients were stratified and treated based on ambulatory BP criteria, and then their incidence of CV events or renal outcomes were captured. IDENTIFICATION OF WHITE-COAT EFFECT AND MASKEDHYPERTENSIVE EFFECT IN TREATED HYPERTENSIVE PATIENTS A substantial proportion of patients with presumed treatmentresistant hypertension based on clinic BP actually are considered to be pseudo-resistant, that is, they exhibit BP that is elevated in the office setting but lower at home (‘white-coat effect’). In a

OFFICE VERSUS AMBULATORY BP REDUCTION IN THERAPEUTIC STUDIES Several studies have monitored patients with both clinic BP measurements and ABPM following drug therapy (Table 2). In a meta-analysis of studies of antihypertensive drugs on BP, in which both clinic and 24-h ABPM were used to monitor patients, Mancia and Parati23 found that the effect of antihypertensive drugs on clinic BP is significantly related to their effect on 24-h BP. However, the effect on the changes of 24-h ambulatory BP is generally smaller than the induced reduction in clinic BP, with reductions in ambulatory BP measuring about 60% of the reductions in clinic BP (14.6/9.2 mm Hg by ABPM versus 24.9/14.5 mm Hg by clinic BP in

Table 1.

Threshold clinic BP and corresponding ambulatory BP values for hypertension grades 1–38 Hypertension severity

Threshold clinic BP (mm Hg)

24-h ambulatory BP (mm Hg)

Daytime BP (mm Hg)

Nighttime BP (mm Hg)

Grade 1 Grade 2 Grade 3

140/90 160/100 180/110

133/84 148/93 163/101

136/87 152/96 168/105

121/76 139/84 157/93

Abbreviation: BP, blood pressure.

Table 2.

Summary of therapeutic studies reporting office versus ambulatory BP reduction

Citation

Study type

Patient no.

Follow-up period

Baseline office BP (mm Hg)

Baseline 24-h BP (mm Hg)

Reduction in office BP (mm Hg)

Reduction in 24h BP (mm Hg)

SBP, 24-h reduction/ office reduction (%)

DBP, 24-h reduction/ office reduction (%)

Mancia and Parati23 Cheng et al.24 Ishikawa et al.25 Staessen et al.26

Meta-analysis

1–144 weeks

161.9/100.2

151.5/94.5

19.1/ 10.3

12.5/ 8.3

65.4

80.6

Meta-analysis

5842 SBP; 5764 DBP 126

8 weeks

152.6/102.6

142.7/94.4

13.7/ 9.9

10/ 6.7

73.0

67.7

Meta-analysis

1246

N/R

15.2/ 10.2

11.9/ 8.5

78.3

83

419

5 weeks–1 year 26 weeks

N/R

Randomized controlled trial

Bakris et al.27

Randomized controlled trial Randomized controlled trial

364 (darusentan group) 20 ABPM; 49 office BP (renal denervation group

14 weeks

CBP group: 164/4/104.0 ABP group: 164.9/102.9 151/88

CBP group: 143.9/89.7a ABP group: 142.5/88.5a 134/78

CBP group: 24.1/ 14.4 ABP group: 20.8/ 13.0 15/ 10

CBP group: 15.9/ 10.6a ABP group: 13.1/ 9.0a 10/ 8

CBP group: 66.0a ABP group: 63.0a 66.7

CBP group: 73.6a ABP group: 69.2a 80.0

6 months

178/96

N/R

32/ 12

11/ 7

34.4

58.3

Esler et al.29

Abbreviations: ABP group, treatment adjusted based on daytime ambulatory BP measurement; ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CBP group, treatment adjusted based on clinic BP measurement; DBP, diastolic BP; N/R, not reported; SBP, systolic BP. aDaytime ambulatory BP.

Journal of Human Hypertension (2013) 715 – 720

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717 studies that lasted more than 24 weeks).23 Additionally, they noted that although reductions in daytime and night-time BP are related, the reduction in night-time BP is almost always substantially less than the daytime reduction. Finally, while patients in the studies generally achieved office systolic BP (SBP) and diastolic BP above and slightly below, respectively, the cutoff value of 140/90 mm Hg for hypertension, BP values measured by 24-h ABPM remained above the corresponding cutoff value of 130/80 mm Hg that is generally used as an ambulatory BP threshold for hypertension.20 For these reasons ‘responders’ cannot be defined by ambulatory BP in the same way as for

Figure 1. Theoretical models of the relationship between 24-h ABPM reduction and office BP reduction.

clinic BP, and a responder should not be expected to have a similar level of BP reduction throughout a 24-h period, as changes in night-time BP are smaller than changes in daytime BP. A similar meta-analysis of three studies of antihypertensive drugs in 126 Chinese patients confirms these results.24 This analysis showed a reduction in both ambulatory BP and clinic BP after 8 weeks of treatment. Baseline clinic BP values (152.6/ 102.6 mm Hg) were higher than baseline 24-h ambulatory BP values (142.7/94.4 mm Hg). Post-treatment clinic BP (138.9/ 92.7 mm Hg) remained higher than post-treatment 24-h ambulatory BP (132.7/87.7 mm Hg). The reduction in BP upon treatment was significantly greater when measured by clinic BP (13.7/9.9 mm Hg) compared with 24-h ABPM (10.0/6.7 mm Hg) (a difference of 3.7/3.2 mm Hg). In a meta-analysis of 30 antihypertensive drug therapy trials, Ishikawa et al.25 analyzed the differences between clinic and home BP monitoring (that is, daily BP self-measurement in morning and evening), and compared home BP results with 24-h ABPM. Their analysis showed that upon antihypertensive therapy, patients achieved a reduction in home BP (12.2/8.0 mm Hg reduction) that was B20% smaller for SBP and 22% smaller for diastolic BP than the drop in clinic BP (15.2/10.3 mm Hg reduction). In addition, when studies that included 24-h ABPM were analyzed, BP reductions upon antihypertensive therapy were even smaller than the drops observed using home BP monitoring. For ambulatory BP readings, daytime SBP reduction was 15% smaller and night-time SBP reduction was 30% smaller than home SBP. As home monitoring eliminates white-coat effect, these results suggest that differences between clinic, home and ambulatory BP readings cannot be explained by white-coat effect alone. The data show that variations in BP over a 24-h period may be significant, and any ‘snapshot,’ either at home or in the office may not provide sufficient information on patients’ BP control. In 419 patients with untreated hypertension, either 24-h ABPM or clinic BP monitoring was utilzed to monitor and adjust antihypertensive treatment.26 Regardless of the method of BP measurement used, reductions in BP at the end of the trial measured by 24-h ABPM were B63–74% of the reductions

Figure 2. Relationship between changes in LVM and clinic or 24-h BP. Conventional clinic systolic blood pressure (CON SBP) versus LVM (a); conventional clinic diastolic blood pressure (CON DBP)versus LVM (b); 24-h systolic blood pressure (24-H SBP) versus LVM (c); 24-h diastolic blood pressure (24-H DBP) versus LVM (d). A reduction of 40 mm Hg by 24-h ABPM results in a greater decrease in LVM than a reduction of 40 mm Hg by clinic BP measurement. Adapted from Fagard et al.4 & 2013 Macmillan Publishers Limited



718 measured by clinic BP. Even when 24-h ABPM is used as a guide to adjust treatment, changes in clinic BP remain greater than changes in 24-h ambulatory BP.26 In 849 patients with treatment-resistant hypertension treated with darusentan, there was no significant difference in BP reduction between placebo and darusentan-treated patients at week 14, due to an unusually strong placebo response. By 24-h ABPM, however, patients treated with darusentan had significantly greater reductions in SBP than placebo-treated patients. In agreement the magnitude of BP reduction by 24-h ABPM was less than the BP reduction as measured by clinic BP. This study, highlights the importance of ABPM in the design of hypertension studies.27 Numerous studies of antihypertensive drug therapies have shown similar trends of BP reductions as measured by clinic BP being greater than those measured by 24-h ABPM.28 Across studies, ambulatory BP reductions in SBP and diastolic BP are roughly 65% and 80% respectively, of clinic BP values. Therefore, 24-h ABPM results cannot be interpreted by the same metric used for clinic BP results because a smaller response must be expected. In light of results of clinical studies on pharmaceutical antihypertensive therapies, it is expected that device-based antihypertensive therapies produce lesser reductions in 24-h ambulatory BP than in clinic BP. Esler et al.29 examined renal denervation in patients with treatment-resistant hypertension and documented a reduction in clinic BP of 32/12 mm Hg 6 months after randomization. In contrast, the reduction in 24-h BP was 11/ 7 mm Hg, but unfortunately it is not specified how much clinic BP was reduced in this small subgroup who underwent 24-h BP monitoring. Importantly, white-coat effect has been associated with sympathetic nervous system overactivity.30–32 Therefore, it is possible that renal denervation, in addition to lowering 24-h BP, also causes a reduction of white-coat effect, which lowers clinic BP even further. Although it is commonly observed in patients with treatment-resistant hypertension, patients with white-coat effects were not excluded from the first renal denervation trials. Therefore, the connection between sympathetic activity and white-coat effect may explain the greater reduction in clinic BP compared with ambulatory BP that was observed after renal denervation.29 An important limitation of current comparisons between clinic BP and 24-h ambulatory BP is that the relationship between the two types of measurements may vary with the severity of hypertension. In other words, we cannot assume that reductions in clinic BP are linearly related to reductions in ambulatory BP. Other models of this relationship should be considered (Figure 1). No mathematical modeling approach has been explored to test whether clinic BP and 24-h BP may have a curvilinear relationship, or perhaps are subject to a threshold effect. Either of these alternative models would advance our understanding of 24-h ABPM results. OFFICE VERSUS AMBULATORY BP: EFFECTS ON TARGET ORGAN DAMAGE AND CV MORTALITY Rather than simply comparing the magnitude of BP reduction as measured by clinic BP and 24-h ABPM, it is now important looking at how each relates to other important outcomes, such as target organ damage and CV mortality.4,30 Unfortunately, there is only evidence available from observational epidemiologic studies. Fagard et al.4 examined the relationship between reduction in BP and reduction in left ventricular mass (LVM). They found that for an equivalent decrease in BP as measured by either of the two methods, the decrease in 24-h ambulatory BP predicted a greater decrease in LVM (Figure 2). For example, a 40 mm Hg decrease in SBP by clinic BP correlated with a 35.9-g reduction in LVM, while a 40 mm Hg decrease in SBP by 24-h ABPM correlated with a 46.4-g reduction in LVM. Journal of Human Hypertension (2013) 715 – 720

Figure 3. Dublin Outcome Study: correlation of clinic and 24-h ambulatory BP with 5-year risk of CV death (n ¼ 5292). A reduction from 180 to 150 mm Hg by clinic BP correlates with a reduction in CV risk from 1.2 to 1.0% (a). The same reduction in CV risk correlates with a smaller change in 24-h BP, from 146 to 136 mm Hg (b). Adapted from Dolan et al.2

In the 5-year-follow-up to the Dublin Outcome Study,2 clinic BP and 24-h ambulatory BP were correlated with risk of CV death. In this study, a 30 mm Hg decrease in clinic SBP, for example, from 180 mm Hg to 150 mm Hg, resulted in a reduction in risk of CV death from B1.2 to 1% (Figure 3a). Conversely, the same reduction in risk of CV death correlated with a decrease of only B10 mm Hg in SBP (from 146 mm Hg to 136 mm Hg) as measured by 24-h ABPM (Figure 3b). The PAMELA Study,33 in which the 11-year-risk of CV death was correlated with BP, shows a similar pattern. In this study, a reduction of 30 mm Hg in clinic SBP (from 180 mm Hg to 150 mm Hg) corresponded with a decrease in risk of CV death from B11 to 5% (Figure 4a). This same reduction in risk of CV & 2013 Macmillan Publishers Limited


719 180 mm Hg, in order to achieve the same reduction in CV event rates, the fall in 24-h ambulatory BP needs to be approximately one-third to one-half the reduction in clinic BP. Twenty-four-hour ABPM is a valuable tool for follow-up and monitoring patients with hypertension. In order to understand their patients’ results, however, clinicians need to be cognizant of the differences between 24-h ABPM and clinic BP. Future research may provide us with better ways to calibrate 24-h ambulatory BP with clinic BP in patients on antihypertensive therapy and related BP reductions. Until then it is important to realize that a much smaller drop in 24-h ambulatory BP than in clinic BP may be required to provide an equivalent reduction in CV events or LVM. CONFLICT OF INTEREST RES has received grants from the University, advisory and speaker honorarium from Astra-Zeneca, Berlin Chemie, Boerhinger Ingelheim, Bristol-Myers Squibb, DaiichiSankyo, Medtronic, Novartis, Servier and Takeda. LR has been advisor/speaker for Astra-Zeneca, Bayer, Boehringer-Ingelheim BMS, Daiichi-Sankyo, GSK, Menarini, Medtronic, Novartis, Servier and Takeda. CO was supported by Deutsche Hochdruckliga. FM has received grants from the University, advisory and speaker honorarium from Berlin Chemie, Boerhinger Ingelheim, Medtronic, Novartis, ReCor, St Jude Medical, Takeda, and Vessix. FM was supported by Deutsche Hochdruckliga, Deutsche Gesellschaft fu¨r Kardiologie und Deutsche Forschungsgemeinschaft (KFO 196). MB was supported by the Deutsche Forschungsgemeinschaft. Grant and research support was provided by Medtronic, St Jude Medical, Boehringer-Ingelheim, Bayer, Pfizer, Novartis. No other relationships or activities that could appear to have influenced the submitted work.

REFERENCES

Figure 4. PAMELA Study: correlation of clinic and 24-h ambulatory BP with 11-year risk of CV death (n ¼ 2051). A reduction from 180 to 150 mm Hg by clinic BP correlates with a reduction in CV risk from 11 to 5% (a). The same reduction in CV risk correlates with a smaller change in 24-h BP, from 151 to 134 mm Hg (b). Adapted from Sega et al.33

death, from 11 to 5%, correlated with a reduction of only 17 mm Hg in SBP (from 151 mm Hg to 134 mm Hg) as measured by 24-h ABPM (Figure 4b). This illustrates the substantial difference in BP reduction that is required to achieve the same mortality risk reduction, depending on the method of BP measurement used. Interestingly, these relationships between risk of CV death and BP measurements are curvilinear for both office BP and 24-h ABPM, including both day and night-time BP monitoring.2,33 Therefore, baseline BP is an important factor in determining the effect that a given reduction of BP will have on CV risk. In other words, for a severely hypertensive patient, a fall of 30 mm Hg in office BP corresponds with a fall in 24-h ABPM of less than half that magnitude. For a moderately hypertensive patient, the reductions that would have to be achieved by each method of BP monitoring would correlate more closely. CONCLUSION On the basis of prospective follow-up studies of treated hypertensive patients with a pretreatment baseline SBP of & 2013 Macmillan Publishers Limited

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