The small changes in BPV observed with treatment were largely overridden by the effect on mean BP, as documented by higher variation coefficient of BP after treatment (Fig. 3 and Supplementary Table 2 and 3, http://links.lww.com/HJH/A871).
Results obtained for day and night BPV were in line with those observed for the 24 h (Supplementary Figure 1 and Supplementary Table 2, http://links.lww.com/HJH/A871).
Despite some negligible discrepancy in the absolute values, the TOVI showed the same trend of smoothness index. No major differences could be seen between the behavior of both measures under different treatments, except that the placebo effect was negligible when evaluated through the TOVI.
Our large pooled individual data analysis of double-blind, randomized, parallel group ABPM studies investigated the effect of olmesartan mono or combination therapy on 24-h BP control, with particular regard to the distribution of the treatment effect and its impact on BPV. Changes in mean 24-h BP were larger under olmesartan monotherapy than under placebo and active control monotherapies, which were based mainly on drugs acting on the renin–angiotensin-aldosterone system. Effects of single-drug treatment were maximal under high dose. In addition, olmesartan administered in combination with one or two other antihypertensive drugs, allowed a superior 24-h BP control than placebo or monotherapies (also including olmesartan). The effect of a combination containing olmesartan was the largest under high dose and no difference in the effect was observed between a dual combination of olmesartan with a dihydropyridine calcium-channel blocker or a thiazide diuretic. The antihypertensive effect achieved with olmesartan or comparators was well maintained during each hour of the 24 h, including the waking period and the night sleep. Treatment with any active drug not only reduced BP mean values but also BPV, in the whole study population as well as in subgroups of patients which are known to be particularly resistant to treatment such as men, elderly or obese patients. The decreasing effect of treatment on BPV is not surprising as it is well known that the degree of decrease in BPV is largely dependent on the extent of BP drop with treatment. Indeed, when we adjusted BPV changes for treatment effect on mean BP, by computing the variation coefficient, the effect of treatment on BPV was almost completely abolished. A multivariate analysis confirmed that the reduction in 24-h BPV with treatment is mainly to be attributed to a reduction in 24-h mean BP level.
Several studies based on 24-h ABPM have shown that antihypertensive drugs decrease ambulatory BPV, a reduction which is proportional to the decrease in mean BP values, suggesting that the effect of antihypertensive treatment on short-term BPV may be largely dependent on the BP lowering, per se [39,40]. In our study we found a collinearity between the reduction in average BP and BPV and in a multivariate analysis the major determinant of the change in BPV was the change in mean BP. However, the relationship was weak (correlation coefficient ranging between 0.06 and 0.19) and thus an independent effect of treatment on BPV cannot be excluded, particularly in case of combination treatments including a dihydropyridine calcium-channel blocker and/or a diuretic. Indeed, the fact that smoothness index and TOVI values, both incorporating information on the effect on mean BP and BPV, were the lowest under placebo and the largest under combination treatment, may suggest that treatment reduced BP but also effectively counteracted the increased BP variability associated with arterial hypertension. The behavior of smoothness index and TOVI in our study also confirms what has been documented in a previous pooled analysis based on another ARB, telmisartan, that these indices provide a robust measure of average BP reduction combined with the assessment of the treatment effect on BPV . Furthermore, although in our study TOVI was characterized by higher values than smoothness index, the differences were only minor, and thus the two estimates may be regarded as interchangeable in their ability to differentiate between treatments. Interestingly, olmesartan always allowed achieving a persistent and smooth BP control over the 24 h, as documented by high values of smoothness index and TOVI in olmesartan-treated patients. The effect was stronger for the dual combination treatment, particularly in the group receiving high drug doses, and even more for the triple combination than for olmesartan monotherapy, indicating a gradual increase of BP lowering and smoothing efficacy.
The duration of BP control was evaluated in our study also by the well known and established TPR. This index exceeded the threshold for adequate BP control (≥0.50) in all treatment groups and was higher in the combination arms. However, a clear differentiation among treatment arms could not be pointed out, as in the case of smoothness index and TOVI. In addition, the TPR was characterized by a substantial placebo effect (0.33 for SBP and 0.42 for DBP), confirming that this popular method for the assessment of the duration of treatment effect is not as sensitive as smoothness index and TOVI for evaluating the 24-h BP-lowering coverage. This is not surprising, as the calculation of TPR concentrates only on two short time intervals, thus potentially missing valuable information relative to the remaining part of the 24 h. It is also affected by variations occurring either spontaneously or resulting from patients’ activities, which make the TPR a rather imprecise estimate of the overall entity and homogeneity of the BP-lowering effect .
The largest reduction of BPV with treatment was observed in our study in patients taking a two or three drug combination treatment, particularly those combinations including a long-acting ARB (olmesartan) and a dihydropyridine calcium-channel blocker (amlodipine or azelnidipine) and/or a thiazide diuretic (hydrochlorothiazide). Such a result could be expected as consistent with literature reporting calcium-channel blockers, mainly belonging to the dihydropyridine class, as the most effective antihypertensive agents in reducing BPV, whereas ARBs and ACE inhibitors (the prevalent drug classes included in the monotherapy group of our study), have a modest effect on this parameter [11,41–43]. The finding that the BPV-lowering effect of olmesartan was enhanced in combination with a dihydropyridine calcium-channel blocker and a thiazide diuretic is in line with the results of a recent study, where the combinations of calcium-channel-blockers with diuretics or ARBs on top of other treatments resulted in lower 24-h BPV vs. other combinations . All this evidence taken together seems to indicate these combinations based on long-acting agents, as the most efficient treatments in lowering BPV in the short term.
In our pooled analysis, short-term BPV was estimated following three popular approaches (unweighted SD, weighted SD, and ARV). Although some numeric differences could be observed across the three methods, the trend of the effect was similar regardless of the methodology employed. Based on our results, we cannot figure out which is the best approach for the evaluation of the effect of treatment on BPV. However, we may hypothesize that the weighted SD and the ARV are superior to the unweighted SD, which incorporates the circadian rhythm of BP. Further studies are demanded to specifically address this methodological question.
We should emphasize that the present study has some limitations. The study is based on a post hoc analysis of 10 studies with some differences in designs and inclusion criteria. Although heterogeneity across the different studies and treatments for baseline BPs and patients’ characteristics were taken into account during statistical comparisons we cannot exclude that such differences may have influenced the results. The fact that we performed an individual data analysis, rather than a summary data meta-analysis, allowed us to adjust the results for possible confounding factors and may reinforce the robustness of our estimates, although the persistence of some bias cannot be excluded. Another limitation of our analysis is that the number of patients in each treatment arm varied widely (from 79 to 1410). However, we weighed such heterogeneity in the size of the study groups by an appropriate analytical approach. The duration of treatment also differed across the studies (from 6 to 12 weeks), although the ranges are compatible with the time required for the considered drugs to develop their activity almost completely. Finally, the number of study participants included in this pooled analysis was less than that presented in the original studies, because we applied more stringent quality criteria for the selection of ABPM data. Such an approach was compulsory, owing to the fact that a reliable assessment of BPV and BP control through smoothness index and TOVI may be achieved only when a consistent number of valid readings and hours is available over the 24 h .
All authors meet the criteria for authorship for this manuscript and gave final approval to the version to be published. S.O. conceived and performed the post hoc analysis, and wrote the manuscript; K.K., G.B., and G.P. critically revised the results of the analysis and the manuscript.
The work was financially supported by Daiichi-Sankyo Europe GmbH through an unconditional and unrestricted grant.
S.O. received a grant for the data analysis and the preparation of the manuscript. K.K., G.B., and G.P. have occasionally received grants for lectures by the manufacturer of olmesartan.
Reviewers’ Summary Evaluations
The paper by Omboni and co-workers gives a comprehensive overview about the effects of olmesartan alone or combined with 1–2 drugs, compared to placebo, active monotherapy or active dual therapy, on 24-h BP reduction and 24-h BP variability. BP variability was evaluated by several indexes providing firm evidence regarding the effect of BP reduction on a better BP variability control. This posthoc analysis involves a very large number of subjects and the authors have correctly applied stringent quality criteria for the selection of ABPM data. I think that the paper is interesting as it is well written, easy to follow and well balanced.
Whether blood pressure variability, in addition to the absolute value of blood pressure, influences life prognosis is a topic that is still being debated. In this study, the authors compare six different treatment groups. While there are different background characteristics among the groups, the number of the subjects in the study is large, and this paper successfully provides comprehensive knowledge by using indicators of several 24-h blood pressure variability such as the variation coefficient and the smoothness index and treatment-on-variability index.
1. Mancia G, Parati G, Hennig M, Flatau B, Omboni S, Glavina F, et al. ELSA Investigators. Relation between blood pressure variability
and carotid artery damage in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens
2. Sega R, Corrao G, Bombelli M, Beltrame L, Facchetti R, Grassi G, et al. Blood pressure variability
and organ damage in a general population: results from the PAMELA study (Pressioni Arteriose Monitorate E Loro Associazioni). Hypertension
3. Shintani Y, Kikuya M, Hara A, Ohkubo T, Metoki H, Asayama K, et al. Ambulatory blood pressure
, blood pressure variability
and the prevalence of carotid artery alteration: the Ohasama study. J Hypertens
4. Madden JM, O’Flynn AM, Fitzgerald AP, Kearney PM. Correlation between short-term blood pressure variability
and left-ventricular mass index: a meta-analysis. Hypertens Res
5. Kikuya M, Hozawa A, Ohokubo T, Tsuji I, Michimata M, Matsubara M, et al. Prognostic significance of blood pressure
and heart rate variabilities: the Ohasama study. Hypertension
6. Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Trevano FQ, et al. Long-term prognostic value of blood pressure variability
in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study. Hypertension
7. Hansen TW, Thijs L, Li Y, Boggia J, Kikuya M, Björklund-Bodegård K, et al. International Database on Ambulatory Blood Pressure
in Relation to Cardiovascular Outcomes Investigators. Prognostic value of reading-to-reading blood pressure variability
over 24 h in 8938 subjects from 11 populations. Hypertension
8. Stolarz-Skrzypek K, Thijs L, Li Y, Hansen TW, Boggia J, Kuznetsova T, et al. Short-term blood pressure variability
in relation to outcome in the International Database of Ambulatory blood pressure
in relation to Cardiovascular Outcome (IDACO). Acta Cardiol
9. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure
, and episodic hypertension. Lancet
10. Stevens SL, Wood S, Koshiaris C, Law K, Glasziou P, Stevens RJ, McManus RJ. Blood pressure variability
and cardiovascular disease: systematic review and meta-analysis. BMJ
11. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, et al. ASCOT-BPLA and MRC Trial Investigators. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure
and risk of stroke. Lancet Neurol
12. Xie HH, Shen FM, Xu LP, Han P, Miao CY, Su DF. Reduction of blood pressure variability
by combination therapy in spontaneously hypertensive rats. J Hypertens
13. Zhang Y, Agnoletti D, Safar ME, Blacher J. Effect of antihypertensive agents on blood pressure variability
: the Natrilix SR versus candesartan and amlodipine in the reduction of systolic blood pressure
in hypertensive patients (X-CELLENT) study. Hypertension
14. Mancia G, Ferrari A, Gregorini L, Parati G, Pomidossi G, Bertinieri G, et al. Blood pressure
and heart rate variabilities in normotensive and hypertensive human beings. Circ Res
15. Bilo G, Giglio A, Styczkiewicz K, Caldara G, Maronati A, Kawecka-Jaszcz K, et al. A new method for assessing 24-h blood pressure variability
after excluding the contribution of nocturnal blood pressure
fall. J Hypertens
16. Mena L, Pintos S, Queipo NV, Aizpúrua JA, Maestre G, Sulbarán T. A reliable index for the prognostic significance of blood pressure variability
. J Hypertens
17. Mena LJ, Maestre GE, Hansen TW, Thijs L, Liu Y, Boggia J, et al. International Database on Ambulatory Blood Pressure
in Relation to Cardiovascular Outcomes (IDACO) Investigators. How many measurements are needed to estimate blood pressure variability
without loss of prognostic information? Am J Hypertens
18. Stolarz-Skrzypek K, Thijs L, Richart T, Li Y, Hansen TW, Boggia J, et al. Blood pressure variability
in relation to outcome in the International Database of Ambulatory blood pressure
in relation to Cardiovascular Outcome. Hypertens Res
19. Parati G, Omboni S, Rizzoni D, Agabiti-Rosei E, Mancia G. The smoothness index
: a new, reproducible and clinically relevant measure of the homogeneity of the blood pressure
reduction with treatment for hypertension. J Hypertens
20. Rizzoni D, Muiesan ML, Salvetti M, Castellano M, Bettoni G, Monteduro C, et al. The smoothness index
, but not the trough-to-peak ratio
predicts changes in carotid artery wall thickness during antihypertensive treatment. J Hypertens
21. Parati G, Dolan E, Ley L, Schumacher H. Impact of antihypertensive combination and monotreatments on blood pressure variability
: assessment by old and new indices. Data from a large ambulatory blood pressure monitoring
database. J Hypertens
22. Scott LJ, McCormack PL. Olmesartan
medoxomil: a review of its use in the management of hypertension. Drugs
23. Tocci G, Paneni F, Passerini J, Volpe M. Triple combination therapy to improve blood pressure
control: experience with olmesartan
-amlodipine-hydrochlorothiazide therapy. Expert Opin Pharmacother
24. Kreutz R. Olmesartan
/amlodipine: a review of its use in the management of hypertension. Vasc Health Risk Manag
25. Omboni S, Malacco E, Mallion JM, Fabrizzi P, Volpe M. Olmesartan
vs. ramipril in elderly hypertensive patients: review of data from two published randomized, double-blind studies. High Blood Press Cardiovasc Prev
26. Omboni S, Malacco E, Mallion JM, Volpe M, Zanchetti A. Study Group. Twenty-four hour and early morning blood pressure
control of olmesartan
vs. ramipril in elderly hypertensive patients: pooled individual data analysis of two randomized, double-blind, parallel-group studies. J Hypertens
27. Püchler K, Laeis P, Stumpe KO. Blood pressure
response, but not adverse event incidence, correlates with dose of angiotensin II antagonist. J Hypertens
2001; 19 (Suppl):S41–S48.
28. Oparil S, Williams D, Chrysant SG, Marbury TC, Neutel J. Comparative efficacy of olmesartan
, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens (Greenwich)
29. Smith DH, Dubiel R, Jones M. Use of 24-h ambulatory blood pressure monitoring
to assess antihypertensive efficacy: a comparison of olmesartan
medoxomil, losartan potassium, valsartan, and irbesartan. Am J Cardiovasc Drugs
30. Brunner HR, Stumpe KO, Januszewicz A. Antihypertensive efficacy of olmesartan
medoxomil and candesartan cilexetil assessed by 24-h ambulatory blood pressure monitoring
in patients with essential hypertension. Clin Drug Investig
31. Brunner HR, Arakawa K. Antihypertensive efficacy of olmesartan
medoxomil and candesartan cilexetil in achieving 24-h blood pressure
reductions and ambulatory blood pressure
goals. Clin Drug Investig
32. Malacco E, Omboni S, Volpe M, Auteri A, Zanchetti A. ESPORT Study Group. Antihypertensive efficacy and safety of olmesartan
medoxomil and ramipril in elderly patients with mild to moderate essential hypertension: the ESPORT study. J Hypertens
33. Mallion JM, Omboni S, Barton J, Van Mieghem W, Narkiewicz K, Panzer PK, et al. Study Group. Antihypertensive efficacy and safety of olmesartan
and ramipril in elderly patients with mild to moderate systolic and diastolic essential hypertension. Blood Press Suppl
34. Ogihara T, Saruta T, Shimada K, Kuramoto K. A randomized, double-blind, four-arm parallel-group study of the efficacy and safety of azelnidipine and olmesartan
medoxomil combination therapy compared with each monotherapy in Japanese patients with essential hypertension: the REZALT study. Hypertens Res
35. Izzo JL Jr, Chrysant SG, Kereiakes DJ, Littlejohn Iii T, Oparil S, Melino M, et al. 24-h efficacy and safety of triple-combination therapy with olmesartan
, amlodipine, and hydrochlorothiazide: the TRINITY ambulatory blood pressure
substudy. J Clin Hypertens (Greenwich)
36. Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartan
medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: the TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study. Clin Ther
37. Parati G, Stergiou G, O’Brien E, Asmar R, Beilin L, Bilo G, et al. European Society of Hypertension Working Group on Blood Pressure
Monitoring and Cardiovascular Variability. European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring
. J Hypertens
38. Omboni S, Parati G, Zanchetti A, Mancia G. Calculation of trough:peak ratio of antihypertensive treatment from ambulatory blood pressure
: methodological aspects. J Hypertens
39. Mancia G, Omboni S, Parati G, Ravogli A, Villani A, Zanchetti A. Lack of placebo effect on ambulatory blood pressure
. Am J Hypertens
40. Parati G, Ochoa JE, Lombardi C, Bilo G. Blood pressure variability
: assessment, predictive value, and potential as a therapeutic target. Curr Hypertens Rep
41. Levi-Marpillat N, Macquin-Mavier I, Tropeano AI, Parati G, Maison P. Antihypertensive drug classes have different effects on short-term blood pressure variability
in essential hypertension. Hypertens Res
42. Hocht C, Del Mauro JS, Bertera FM, Taira CA. Drugs affecting blood pressure variability
: an update. Curr Pharm Des
43. Eguchi K. Effects of antihypertensive therapy on blood pressure variability
. Curr Hypertens Rep