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Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status
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Original research article
Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status Wojciech Sobiczewski a, Marcin Wirtwein b,*, Marcin Gruchała a, Ivan Kocic´ b a b
I Department of Cardiology, Medical University of Gdansk, Gdan´sk, Poland Department of Pharmacology, Medical University of Gdansk, Gdansk, Poland
A R T I C L E I N F O
Article history: Received 10 August 2013 Received in revised form 30 November 2013 Accepted 16 December 2013 Available online xxx Keywords: Hypertension Chronopharmacotherapy Coronary heart disease Blood pressure profile Non-dippers
A B S T R A C T
Background: The goal of our study was to assess the influence of hypertension chronopharmacotherapy on diurnal blood pressure (BP) profile and mortality. Methods: Subjects with established coronary heart disease (CHD) (n = 1345, mean age 63.2 9.2 years) were included. Results: Non-dipping status was related to a lack of nighttime hypertensive drug administration (OR 3.87, 95% CI 3.00–4.98). In a Cox proportional hazards regression model, non-dipping status (HR 1.17, 95% CI 1.02–1.47) and non-nighttime antihypertensive drug administration (HR 1.13, 95% CI 1.01–1.45) were predictors of all-cause mortality. Conclusions: The non-dipping profile of CHD patients and increased mortality were related to a lack of antihypertensive drug administration at bedtime. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Introduction The efficacy of hypertension medications is strongly related to their pharmacokinetic and pharmacodynamic properties, and the associated frequency of administration. Ambulatory blood pressure monitoring (ABPM) is especially useful in defining the efficacy of hypertensive medications not only due to the recording of daytime blood pressure (BP) values, but also due to the measurement of nighttime BP values in particular [1–3]. Numerous studies have consistently shown that blunted nighttime BP dipping is related to increased fatal cardiovascular (CV) events [4– 6]. Therefore, antihypertensive therapy should focus not only on the normalization of BP values, but also on normalization of BP variability [7]. Previously performed clinical trials have revealed that among subjects taking antihypertensive medications and achieving therapeutic goals, there is group of patients with blunted sleep-time dipping that is related to an high CV risk [8]. This phenomenon might be related to improper time-regimen of antihypertensive drug administration resulting from a disregard for the duration of action of these medications. Moreover, according to previously performed clinical trials, hypertensive
* Corresponding author. E-mail address: [email protected] (M. Wirtwein).
subjects with established coronary heart disease (CHD) have a higher probability of blunted sleep-time dipping of BP [6,9]. Therefore, not complying with the principles of hypertension chronopharmacotherapy may be associated with an increased CV risk in already-treated hypertensives, especially those with CHD. Thus, the main purpose of our study was to evaluate the influence of chronopharmacotherapy on diurnal BP control in treated hypertensive patients with CHD. Additionally, we assessed the relationship between diurnal blood pressure profile and total mortality in hypertensives with CHD in over a seven-year observation period. Materials and methods Subjects The observational study recruited 1345 consecutive CHD individuals (between August 2003 and August 2006) with typical angina symptoms and/or signs of myocardial ischemia identified in non-invasive diagnostic procedures (ECG stress test, dobutamine stress echocardiography or myocardial perfusion scyntygraphy stress test) in order to evaluate the indication for invasive treatment (PCI or CABG) in coronary angiography. Subjects with atrial fibrillation or atrial flutter, congestive heart failure of NYHA class III or IV, significant valvular heart disease or valvular heart
http://dx.doi.org/10.1016/j.pharep.2013.12.009 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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disease qualifying the patient for cardiosurgery, renal insufficiency with a creatinine level 2.0 mg/dL, changes in pharmacotherapy of hypertension within six months before 24-h ambulatory BP monitoring, and other chronic diseases leading to limited life expectancy were excluded. Blood pressure measurements To avoid the influence on BP of either hospital conditions or the need for reduced physical activity, in a period of two to four weeks after coronary angiography 24-h ambulatory BP monitoring was obtained (SpaceLabs 90210, SpaceLabs Inc., Redmond, WA, USA) with BP readings set at 20-min intervals (6:00 a.m.–6:00 p.m.) and at 30-min intervals (6:00 p.m.–6:00 a.m.). The non-dominant arm was used for measurement with cuff size adjusted to arm circumference (adult cuff 27–34 cm or large adult cuff 35– 44 cm). All BP recordings were obtained on working days, and patients were instructed to maintain their usual activities but to refrain from strenuous exercise and emotional burden. Patients were instructed to hold their arm still by their side during blood pressure measurement and to return to the hospital 24 h later. Participants had no access to their ambulatory BP values. BP measurements recorded between 8:00 and 22:00 were considered as daytime BP values, and BP measurements recorded between 0:00 and 6:00 were considered as nighttime BP values. The percentage decrease in mean systolic BP during the nighttime period was calculated as 100 [daytime systolic BP mean nighttime systolic BP mean]/daytime systolic BP mean. Using this percentage ratio, subjects were classified as dippers or nondippers (nighttime relative systolic BP decline or <10%, respectively) [2]. Office BP measurements were performed just before ambulatory BP measurements using a validated oscillometric device (OMRON 705 IT) with the cuff fitted to arm circumference. BP was measured on the non-dominant arm.
subjects’ treatment for hypertension. Decisions about the pharmacotherapy of hypertension were made on the basis of clinic BP measurements. All the doctors had European Society of Hypertension guidelines at their disposal. After considering the doses of antihypertensive drugs and their altered effectiveness due to combined therapy, all medications used in the treatment of the included subjects had a trough-to-peak (TTP) ratio (calculated as the ratio between the values of BP at max drop point and just before giving the next dose of antihypertensive drug) in the range of 50–80%. Laboratory tests On admission day before a coronary angiography, fasting blood samples were collected in order to measure total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides levels, and serum creatinine level. Assessment of coronary atherosclerosis The coronary angiography was performed in the Department of Invasive Cardiology, and angiograms were evaluated independently by two experienced invasive cardiologists. The coronary angiography was used to confirm coronary atherosclerosis. Follow-up period Subjects were followed from the date of coronary angiography until December 31, 2011. Follow-up was performed during visits to the clinic, and if patients were unable to attend they were contacted by phone. Data about coronary revascularization (PCI or CABG) was verified by the review of discharge cards and procedure protocols. Stroke diagnosis was performed according to European Stroke Organization guidelines, and acute coronary syndromes (ACS) were diagnosed according to European Society of Cardiology guidelines [10–12]. CV events included acute coronary syndromes (myocardial infarction or unstable angina) and stroke.
Antihypertensive therapy Statistical analysis All subjects were treated with antihypertensive drugs. None of the subjects had had a change in pharmacotherapy in the six-month period before ambulatory blood pressure measurement. Pharmacological therapy had been established by general practitioners or cardiologists who were involved in treatment of hypertension in the
The overarching goal of the analysis was to create a statistical model to assess the influence of pharmacotherapy on diurnal BP variations. A logistic regression model was used for this purpose. We also performed an analysis of mortality in the follow-up period
Table 1 Basic characteristics the studied groups.
Male, n Age, years Diabetes, n Smokers, n Total cholesterol, mg/dL LDL cholesterol mg/DL HDL cholesterol mg/dL Triglycerides mg/dL Clinic systolic BP (mmHg) Clinic diastolic BP (mmHg) Clinic heart rate (bpm) Daytime systolic BP (mmHg) Daytime diastolic BP (mmHg) Daytime heart rate (bpm) Nighttime systolic BP (mmHg) Nighttime diastolic BP (mmHg) Nighttime heart rate (bpm) Clinic BP 140/90 mmHg, n Daytime BP 135/85 mmHg, n Nighttime BP 120/70 mmHg, n
Total group n = 1345
Dippers n = 600
Non dippers n = 745
p
820 (61%) 63.2 9.2 279 (21%) 208 (15%) 205.2 52.2 120.5 43.0 55.3 13.6 147.6 99.5 137.7 20.1 78.3 11.3 70.5 12.1 127.1 14.0 74.3 8.7 69.6 10.5 119.0 15.4 66.4 8.9 61.9 8.9 496 (37%) 416 (31%) 634 (47%)
366 (61%) 61.5 9.3 108 (18%) 96 (16%) 211.7 51.5 126.2 44.8 55.5 13.3 153.7 103.5 139.1 19.5 80.4 10.4 71.2 12.3 128.7 13.3 76.7 8.1 71.4 11.3 110.4 11.7 62.8 7.1 62.3 9.6 153 (38%) 222 (37%) 180 (30%)
454 (61%) 64.0 9.1 171 (23%) 112 (15%) 202.5 53.2 118.3 42.1 55.2 13.8 145.0 98.0 137.1 20.3 77.3 11.5 70.3 12.0 126.4 14.2 73.4 8.8 68.9 10.1 122.7 15.3 67.9 9.1 61.7 8.6 268 (36%) 194 (26%) 454 (61%)
ns <0.01 0.04 ns <0.01 <0.01 ns ns ns <0.01 ns <0.01 <0.01 <0.01 <0.01 <0.01 ns ns <0.01 <0.001
LDL – low density lipoprotein, HDL – high density lipoprotein, BP – blood pressure.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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Table 2 Medications in the studied groups.
ASA, n Lipid-lowering drugs, n Nitrate, n b-Blockers, n Calcium channel blockers, n ACE-I, n ARBs, n Diuretics, n a-Blockers, n Other medications, n One medication, n Two medications, n Three or more medications, n Two or more medications with diuretic, n Median of medications Only morning administration of drugs, n Only evening administration of drugs, n Twice a day administration of drugs, n Three or more times a day administration of drugs, n
Total group n = 1345
Dippers n = 600
Non dippers n = 745
p
1052 1230 420 1033 336 982 61 167 55 100 344 677 324 196 2 664 138 272 271
456 552 174 444 150 438 24 78 18 48 150 312 138 84 2 180 78 168 174
596 678 246 589 186 544 37 89 37 52 194 365 186 112 2 484 60 104 97
ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns <0.01 ns <0.03 <0.01
(78%) (91%) (31%) (77%) (25%) (73%) (4%) (12%) (4%) (7%) (26%) (50%) (24%) (15%) (50%) (10%) (20%) (20%)
(76%) (92%) (29%) (74%) (25%) (73%) (4%) (13%) (3%) (8%) (25%) (52%) (23%) (14%) (30%) (13%) (28%) (29%)
(80%) (91%) (33%) (79%) (25%) (73%) (5%) (12%) (5%) (7%) (26%) (49%) (25%) (15%) (65%) (8%) (14%) (13%)
ASA – acetylosalicylic acid, lipid lowering drugs include statins and fibrates, ACE-I – inhibitors of angiotensin converting enzyme, ARBs – angiotensin receptor blockers.
using BP dipping status as one of the BP diurnal variability parameters. A Cox proportional model was used for this goal. In order to compare continuous variables, a t-Student test or a UMann–Whitney test were used as appropriate. For categorical variables an x2 test was used. Continuous variables were reported as mean standard deviation, and categorical variables were reported as percentages, p < 0.05 was taken as the level of statistical significance. Statistical analyses were performed using STATISTICA version 10 (Tulsa, OK 74104, USA) and R version 3.0.1. The study protocol was approved by the Ethics Committee of the Medical University of Gdansk.
Results After considering the inclusion and exclusion criteria, 1345 out of 1908 consecutive patients admitted for elective coronary angiography were included in the study. We excluded 563 (28%) patients due to the following reasons: atrial fibrillation or atrial flutter (n = 138; 7%), congestive heart failure of NYHA class III or IV (n = 97; 5%), significant valvular heart disease or valvular heart disease qualifying the patient for cardiosurgery (n = 123; 6%), renal insufficiency with a creatinine level 2.0 mg/dL (n = 83; 4%), and other chronic diseases leading to limited life expectancy (n = 122;
Table 3 Monotherapy and combined therapy of hypertension in the studied groups. Total group n = 1345
Dippers n = 600
Monotherapy b-Blockers Calcium channel blockers ACE-I/ARB Diuretics a-Blockers Other medications
102 13 67 1 3 19
(8%) (1%) (5%) (0.1%) (0.3%) (1%)
42 6 30 0 0 12
(7%) (1%) (5%)
Two drug therapy b-Blocker + ACEI/ARB Calcium channel blockers + ACEI/ARB Diuretic + ACEI/ARB b-Blocker + Calcium channel blocker b-Blocker + Diuretic b-Blocker + a-blocker Calcium channel blocker + Diuretic ACE-I/ARB + a-blockers b-Blocker + other
538 60 19 21 13 6 1 3 20
(40%) (4%) (1%) (2%) (1%) (0.5%) (0.1%) (0.2%) (1%)
240 30 12 13 5 0 1 0 10
(40%) (5%) (2%) (2%) (1%)
205 114 27 6 6 18 3 1
(15%) (8%) (2%) (0.5%) (0.5%) (1%) (0.2%) (0.1%)
78 54 12 2 2 6 0 0
(13%) (9%) (2%) (0.3%) (0.3%) (1%)
(2%)
(0.2%) (2%)
Non dippers n = 745
p
60 7 37 1 3 7
(8%) (1%) (5%) (0.1%) (0.3%) (1%)
ns ns ns
298 30 7 8 8 6 0 3 10
(40%) (4%) (1%) (1%) (1%) (1%)
ns ns ns ns ns
127 60 15 4 4 12 3 1
(17%) (8%) (2%) (0.5%) (0.5%) (2%) (0.4%) (0.1%)
(0.4%) (1%)
ns
ns
Three drug therapy
b-Blocker + ACEI/ARB + Calcium channel blocker b-Blocker + ACEI/ARB + Diuretic b-Blocker + ACEI/ARB + a-blocker b-Blocker + Calcium channel blocker + Diuretic Calcium channel blockers + ACEI/ARB + a-blocker Calcium channel blockers + ACEI/ARB + Diuretic ACE-I/ARB + a-blockers + Diuretic b-Blocker + a-blocker + Diuretic More than three medications
81 (6%)
36 (6%)
45 (6%)
ns ns ns ns ns ns
ns
ASA – acetylosalicylic acid, lipid lowering drugs include statins and fibrates, ACE-I-inhibitors – inhibitors of angiotensin converting enzyme, ARBs – angiotensin receptor blockers.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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Table 4 Multiple logistic regression model for non-dipping status as response variable. Variable Intercept Age Diabetes No nighttime drug administration Office BP 140/90 mmHg
b coefficient 2.24 0.20 0.50 1.35 0.17
Standard error
Wald x2
p value
Odds ratio
95% CI
0.45 0.01 0.15 0.13 0.13
– 7.56 10.78 110.3 1.71
– <0.01 <0.01 <0.01 0.19
– 2.97 1.64 3.87 1.18
– 1.37–6.47 1.22–2.21 3.00–4.98 0.91–1.82
SBP – systolic blood pressure, CI – confidence interval.
Table 5 A Cox proportional hazards regression model showing the effect of age, diabetes, dipping status, clinic, daytime and nighttime BP thresholds and bedtime administration of antihypertensive drugs on the risk of all-cause mortality. Variable
b coefficient
Standard error
Wald x2
p value
Hazard ratio
95% CI
Age Diabetes Non dippers No nighttime drug administration Office BP 140/90 mmHg Daytime BP 135/85 mmHg Nighttime BP 120/70 mmHg
0.03 0.29 0.25 0.21 0.21 0.06 0.23
0.01 0.09 0.08 0.07 0.09 0.11 0.10
12.6 11.5 10.8 8.3 0.05 0.29 8.7
<0.01 <0.01 <0.03 <0.04 0.80 0.58 <0.03
1.03 1.79 1.17 1.13 1.04 1.12 1.25
1.01–1.05 1.28–2.52 1.02–1.47 1.01–1.45 0.73–1.50 0.74–1.70 1.03–1.91
SBP – systolic blood pressure, CI – confidence interval.
6%). There has been no change in antihypertensive pharmacotherapy for all included patients in the six month period before inclusion. Non-dipper patients accounted for 55% of the study population. Baseline characteristics of the total group as well as dippers and non-dippers are outlined in Table 1. The median follow-up period was 6.6 years (interquartile range 6.1–7.1 years). Qualitative analysis of medications did not reveal differences in the antihypertensive drugs used. Dippers and non-dippers differed in frequency of antihypertensive drugs administration i.e. in higher percentage of non-dippers antihypertensive drugs were administrated only in the morning but in lower percentage of non-dippers antihypertensive drugs were administrated twice or three times a day in comparison to dippers (Table 2). The studied groups did not differ in combined pharmacotherapy of hypertension (Table 3). A logistic regression model revealed the relationship between nonnighttime drug administration and non-dipping status (Table 4). A Cox proportional hazards regression model showed that nondipping status and non-nighttime pharmacotherapy of hypertension were connected with a higher risk of all-cause mortality in the studied population (Table 5). Discussion In this long-term single-centre study on patients with symptomatic CHD, we demonstrated that frequency of administration of antihypertensive drugs was different for non-dipper subjects and for dippers. Moreover, we revealed that non-dipping status was related to a lack of medications administration at bedtime. But the most important clinical implication is connected with the impact of non-dipping status and the lack of a nighttime medication administration regimen on mortality. O’Brien at al. first identified a group of hypertensive patients with blunted nighttime BP decrease and named them as nondippers [13]. Many clinical trials showed that this profile of BP is connected with a higher risk of CV events even in hypertensive patients with well-controlled BP [14]. Dauphinot et al. showed that in untreated hypertensive patients, non-dipping status was related to impaired autonomic nervous system activity [15]. But in treated hypertensive patients the impact of autonomic nervous system activity on circadian blood pressure profile might be distorted by antihypertensive medications. Hermida et al. revealed that in patients included in the Hygia Project circadian BP profile was
related to the treatment-time regimen of antihypertensive medications [16]. Our results confirmed these observations in the group of patients with established CHD. Moreover, instead of no differences between non-dippers and dippers in the quantity of drugs used and their combinations, we showed that non-dipping status was related to a less frequent bedtime administration of antihypertensive drugs. In our study, age, diabetes and non nighttime drug administration were determinants of non-dipping status. Among these variables, no nighttime drug administration increased the risk of non-dipping status by about four times. This seemingly obvious relationship is often overlooked in the determination of antihypertensive therapy. This fact may be the reason for sub-optimal BP control and the lack of decline in organ damage complications related to hypertension in recent years, despite increased intensity of therapy and the many new drugs approved for the therapy of hypertension [17,18]. It should be emphasized that the TTP ratio for all drugs used and their combinations was between 50% and 80%. Therefore, antihypertensive medications which were administrated only once a day did not provide total diurnal BP control. Although TTP was assessed for many antihypertensive drugs and their combinations, and was approved as a clinical parameter defining duration of action, it seems that physicians do not use it in clinical practice. In the context of our results, administration of antihypertensive drugs with a too low TTP could be one of the reasons for the high prevalence of non-dipping profile in the studied population, and might be one of the reasons for higher mortality in patients with blunted nighttime BP decrease. In the present study, there was a higher percentage of hypertensive patients with daytime BP in just over the target thresholds, but a lower percentage of patients with nighttime BP in over the target thresholds among dippers than non-dippers. However, there was no difference in the percentage of patients in over the target thresholds of clinic BP. This finding is important in determining pharmacological treatment on the basis of timeunspecified single clinic BP measurements. Hermida et al. revealed that an antihypertensive treatment regimen based on only clinic BP is both less effective and related to higher cardiovascular risk than using ABPM values when determining hypertension therapy in individual patients [19–21]. Our study has indirectly confirmed these findings in CHD patients with hypertension. We have
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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revealed that non-nighttime drug administration is related to higher risk in all-cause mortality. Moreover, neither overthreshold clinic BP nor over threshold daytime BP were significantly associated with risk of all-cause deaths. This finding might be explained by relatively satisfactory clinic and daytime BP control in the study group. But only over-nighttime BP threshold was related to higher all-cause mortality. On the other hand overdaytime BP threshold did not predict all-cause mortality in the study. Our results have important clinical implications. The use of information provided by ABPM, especially nighttime BP and diurnal BP variability, may lead to a greater reduction in mortality in CHD patients. In conclusion, our study confirmed that the non-dipping profile of CHD patients is related to the lack of administration of antihypertensive drugs with a relatively short TTP at bedtime. Moreover, pharmacotherapy based only on clinic BP measurements does not reduce mortality resulting from inappropriate BP diurnal rhythm. Wider use of ABPM devices by physicians might lead to a reduction in mortality caused by inappropriate BP diurnal rhythm. Conflict of interest No conflict of interest for all authors. There are no relationships with industry. Funding This study was supported by state committee for scientific research – KBN 2 P05B12727 from the Ministry of National Education in Poland. References [1] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care 2011;34:1270–6. [2] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol 2011;22:2313–21. [3] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int 2010;27:1629–51. [4] Boggia J, Li Y, Thijs L, Hansen TW, Kikuya M, Bjorklund-Bodegard K, et al. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 2007;370:1219–29.
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[5] Brotman DJ, Davidson MB, Boumitri M, Vidt DG. Impaired diurnal blood pressure variation and all-cause mortality. Am J Hypertens 2008;21:92–7. [6] Hermida RC, Ayala DE, Fernandez JR, Mojon A. Sleep-time blood pressure: prognostic value and relevance as a therapeutic target for cardiovascular risk reduction. Chronobiol Int 2013;30:68–86. [7] Hermida RC, Smolensky MH, Ayala DE, Portaluppi F. 2013 ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals. Chronobiol Int 2013;30:355–410. [8] Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213–25. [9] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J Am Coll Cardiol 2011;58:1165–73. [10] Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809–40. [11] Olsen TS, Langhorne P, Diener HC, Hennerici M, Ferro J, Sivenius J, et al. European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis 2003;16:311–37. [12] Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al. Management of acute myocardial infarction in patients presenting with STsegment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24: 28–66. [13] O’Brien E, Sheridan J, O’Malley K. Dippers and non-dippers. Lancet 1988;2:397. [14] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Blunted sleep-time relative blood pressure decline increases cardiovascular risk independent of blood pressure level-the ‘‘normotensive non-dipper’’ paradox. Chronobiol Int 2013;30:87–98. [15] Dauphinot V, Gosse P, Kossovsky MP, Schott AM, Rouch I, Pichot V, et al. Autonomic nervous system activity is independently associated with the risk of shift in the non-dipper blood pressure pattern. Hypertens Res 2010;33:1032–7. [16] Hermida RC, Rios MT, Crespo JJ, Moya A, Dominguez-Sardina M, Otero A, et al. Treatment-time regimen of hypertension medications significantly affects ambulatory blood pressure and clinical characteristics of patients with resistant hypertension. Chronobiol Int 2013;30:192–206. [17] Catala-Lopez F, Sanfelix-Gimeno G, Garcia-Torres C, Ridao M, Peiro S. Control of arterial hypertension in Spain: a systematic review and meta-analysis of 76 epidemiological studies on 341 632 participants. J Hypertens 2012;30: 168–76. [18] Tocci G, Rosei EA, Ambrosioni E, Borghi C, Ferri C, Ferrucci A, et al. Blood pressure control in Italy: analysis of clinical data from 2005–2011 surveys on hypertension. J Hypertens 2012;30:1065–74. [19] Hermida RC, Ayala DE, Calvo C, Portaluppi F, Smolensky MH. Chronotherapy of hypertension: administration-time-dependent effects of treatment on the circadian pattern of blood pressure. Adv Drug Deliv Rev 2007;59:923–39. [20] Hermida RC, Ayala DE, Calvo C. Administration-time-dependent effects of antihypertensive treatment on the circadian pattern of blood pressure. Curr Opin Nephrol Hypertens 2005;14:453–9. [21] Portaluppi F, Hermida RC. Circadian rhythms in cardiac arrhythmias and opportunities for their chronotherapy. Adv Drug Deliv Rev 2007;59:940–51.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
PHAREP-73; No. of Pages 5 Pharmacological Reports xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Original research article
Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status Wojciech Sobiczewski a, Marcin Wirtwein b,*, Marcin Gruchała a, Ivan Kocic´ b a b
I Department of Cardiology, Medical University of Gdansk, Gdan´sk, Poland Department of Pharmacology, Medical University of Gdansk, Gdansk, Poland
A R T I C L E I N F O
Article history: Received 10 August 2013 Received in revised form 30 November 2013 Accepted 16 December 2013 Available online xxx Keywords: Hypertension Chronopharmacotherapy Coronary heart disease Blood pressure profile Non-dippers
A B S T R A C T
Background: The goal of our study was to assess the influence of hypertension chronopharmacotherapy on diurnal blood pressure (BP) profile and mortality. Methods: Subjects with established coronary heart disease (CHD) (n = 1345, mean age 63.2 9.2 years) were included. Results: Non-dipping status was related to a lack of nighttime hypertensive drug administration (OR 3.87, 95% CI 3.00–4.98). In a Cox proportional hazards regression model, non-dipping status (HR 1.17, 95% CI 1.02–1.47) and non-nighttime antihypertensive drug administration (HR 1.13, 95% CI 1.01–1.45) were predictors of all-cause mortality. Conclusions: The non-dipping profile of CHD patients and increased mortality were related to a lack of antihypertensive drug administration at bedtime. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Introduction The efficacy of hypertension medications is strongly related to their pharmacokinetic and pharmacodynamic properties, and the associated frequency of administration. Ambulatory blood pressure monitoring (ABPM) is especially useful in defining the efficacy of hypertensive medications not only due to the recording of daytime blood pressure (BP) values, but also due to the measurement of nighttime BP values in particular [1–3]. Numerous studies have consistently shown that blunted nighttime BP dipping is related to increased fatal cardiovascular (CV) events [4– 6]. Therefore, antihypertensive therapy should focus not only on the normalization of BP values, but also on normalization of BP variability [7]. Previously performed clinical trials have revealed that among subjects taking antihypertensive medications and achieving therapeutic goals, there is group of patients with blunted sleep-time dipping that is related to an high CV risk [8]. This phenomenon might be related to improper time-regimen of antihypertensive drug administration resulting from a disregard for the duration of action of these medications. Moreover, according to previously performed clinical trials, hypertensive
* Corresponding author. E-mail address: [email protected] (M. Wirtwein).
subjects with established coronary heart disease (CHD) have a higher probability of blunted sleep-time dipping of BP [6,9]. Therefore, not complying with the principles of hypertension chronopharmacotherapy may be associated with an increased CV risk in already-treated hypertensives, especially those with CHD. Thus, the main purpose of our study was to evaluate the influence of chronopharmacotherapy on diurnal BP control in treated hypertensive patients with CHD. Additionally, we assessed the relationship between diurnal blood pressure profile and total mortality in hypertensives with CHD in over a seven-year observation period. Materials and methods Subjects The observational study recruited 1345 consecutive CHD individuals (between August 2003 and August 2006) with typical angina symptoms and/or signs of myocardial ischemia identified in non-invasive diagnostic procedures (ECG stress test, dobutamine stress echocardiography or myocardial perfusion scyntygraphy stress test) in order to evaluate the indication for invasive treatment (PCI or CABG) in coronary angiography. Subjects with atrial fibrillation or atrial flutter, congestive heart failure of NYHA class III or IV, significant valvular heart disease or valvular heart
http://dx.doi.org/10.1016/j.pharep.2013.12.009 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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disease qualifying the patient for cardiosurgery, renal insufficiency with a creatinine level 2.0 mg/dL, changes in pharmacotherapy of hypertension within six months before 24-h ambulatory BP monitoring, and other chronic diseases leading to limited life expectancy were excluded. Blood pressure measurements To avoid the influence on BP of either hospital conditions or the need for reduced physical activity, in a period of two to four weeks after coronary angiography 24-h ambulatory BP monitoring was obtained (SpaceLabs 90210, SpaceLabs Inc., Redmond, WA, USA) with BP readings set at 20-min intervals (6:00 a.m.–6:00 p.m.) and at 30-min intervals (6:00 p.m.–6:00 a.m.). The non-dominant arm was used for measurement with cuff size adjusted to arm circumference (adult cuff 27–34 cm or large adult cuff 35– 44 cm). All BP recordings were obtained on working days, and patients were instructed to maintain their usual activities but to refrain from strenuous exercise and emotional burden. Patients were instructed to hold their arm still by their side during blood pressure measurement and to return to the hospital 24 h later. Participants had no access to their ambulatory BP values. BP measurements recorded between 8:00 and 22:00 were considered as daytime BP values, and BP measurements recorded between 0:00 and 6:00 were considered as nighttime BP values. The percentage decrease in mean systolic BP during the nighttime period was calculated as 100 [daytime systolic BP mean nighttime systolic BP mean]/daytime systolic BP mean. Using this percentage ratio, subjects were classified as dippers or nondippers (nighttime relative systolic BP decline or <10%, respectively) [2]. Office BP measurements were performed just before ambulatory BP measurements using a validated oscillometric device (OMRON 705 IT) with the cuff fitted to arm circumference. BP was measured on the non-dominant arm.
subjects’ treatment for hypertension. Decisions about the pharmacotherapy of hypertension were made on the basis of clinic BP measurements. All the doctors had European Society of Hypertension guidelines at their disposal. After considering the doses of antihypertensive drugs and their altered effectiveness due to combined therapy, all medications used in the treatment of the included subjects had a trough-to-peak (TTP) ratio (calculated as the ratio between the values of BP at max drop point and just before giving the next dose of antihypertensive drug) in the range of 50–80%. Laboratory tests On admission day before a coronary angiography, fasting blood samples were collected in order to measure total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides levels, and serum creatinine level. Assessment of coronary atherosclerosis The coronary angiography was performed in the Department of Invasive Cardiology, and angiograms were evaluated independently by two experienced invasive cardiologists. The coronary angiography was used to confirm coronary atherosclerosis. Follow-up period Subjects were followed from the date of coronary angiography until December 31, 2011. Follow-up was performed during visits to the clinic, and if patients were unable to attend they were contacted by phone. Data about coronary revascularization (PCI or CABG) was verified by the review of discharge cards and procedure protocols. Stroke diagnosis was performed according to European Stroke Organization guidelines, and acute coronary syndromes (ACS) were diagnosed according to European Society of Cardiology guidelines [10–12]. CV events included acute coronary syndromes (myocardial infarction or unstable angina) and stroke.
Antihypertensive therapy Statistical analysis All subjects were treated with antihypertensive drugs. None of the subjects had had a change in pharmacotherapy in the six-month period before ambulatory blood pressure measurement. Pharmacological therapy had been established by general practitioners or cardiologists who were involved in treatment of hypertension in the
The overarching goal of the analysis was to create a statistical model to assess the influence of pharmacotherapy on diurnal BP variations. A logistic regression model was used for this purpose. We also performed an analysis of mortality in the follow-up period
Table 1 Basic characteristics the studied groups.
Male, n Age, years Diabetes, n Smokers, n Total cholesterol, mg/dL LDL cholesterol mg/DL HDL cholesterol mg/dL Triglycerides mg/dL Clinic systolic BP (mmHg) Clinic diastolic BP (mmHg) Clinic heart rate (bpm) Daytime systolic BP (mmHg) Daytime diastolic BP (mmHg) Daytime heart rate (bpm) Nighttime systolic BP (mmHg) Nighttime diastolic BP (mmHg) Nighttime heart rate (bpm) Clinic BP 140/90 mmHg, n Daytime BP 135/85 mmHg, n Nighttime BP 120/70 mmHg, n
Total group n = 1345
Dippers n = 600
Non dippers n = 745
p
820 (61%) 63.2 9.2 279 (21%) 208 (15%) 205.2 52.2 120.5 43.0 55.3 13.6 147.6 99.5 137.7 20.1 78.3 11.3 70.5 12.1 127.1 14.0 74.3 8.7 69.6 10.5 119.0 15.4 66.4 8.9 61.9 8.9 496 (37%) 416 (31%) 634 (47%)
366 (61%) 61.5 9.3 108 (18%) 96 (16%) 211.7 51.5 126.2 44.8 55.5 13.3 153.7 103.5 139.1 19.5 80.4 10.4 71.2 12.3 128.7 13.3 76.7 8.1 71.4 11.3 110.4 11.7 62.8 7.1 62.3 9.6 153 (38%) 222 (37%) 180 (30%)
454 (61%) 64.0 9.1 171 (23%) 112 (15%) 202.5 53.2 118.3 42.1 55.2 13.8 145.0 98.0 137.1 20.3 77.3 11.5 70.3 12.0 126.4 14.2 73.4 8.8 68.9 10.1 122.7 15.3 67.9 9.1 61.7 8.6 268 (36%) 194 (26%) 454 (61%)
ns <0.01 0.04 ns <0.01 <0.01 ns ns ns <0.01 ns <0.01 <0.01 <0.01 <0.01 <0.01 ns ns <0.01 <0.001
LDL – low density lipoprotein, HDL – high density lipoprotein, BP – blood pressure.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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Table 2 Medications in the studied groups.
ASA, n Lipid-lowering drugs, n Nitrate, n b-Blockers, n Calcium channel blockers, n ACE-I, n ARBs, n Diuretics, n a-Blockers, n Other medications, n One medication, n Two medications, n Three or more medications, n Two or more medications with diuretic, n Median of medications Only morning administration of drugs, n Only evening administration of drugs, n Twice a day administration of drugs, n Three or more times a day administration of drugs, n
Total group n = 1345
Dippers n = 600
Non dippers n = 745
p
1052 1230 420 1033 336 982 61 167 55 100 344 677 324 196 2 664 138 272 271
456 552 174 444 150 438 24 78 18 48 150 312 138 84 2 180 78 168 174
596 678 246 589 186 544 37 89 37 52 194 365 186 112 2 484 60 104 97
ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns <0.01 ns <0.03 <0.01
(78%) (91%) (31%) (77%) (25%) (73%) (4%) (12%) (4%) (7%) (26%) (50%) (24%) (15%) (50%) (10%) (20%) (20%)
(76%) (92%) (29%) (74%) (25%) (73%) (4%) (13%) (3%) (8%) (25%) (52%) (23%) (14%) (30%) (13%) (28%) (29%)
(80%) (91%) (33%) (79%) (25%) (73%) (5%) (12%) (5%) (7%) (26%) (49%) (25%) (15%) (65%) (8%) (14%) (13%)
ASA – acetylosalicylic acid, lipid lowering drugs include statins and fibrates, ACE-I – inhibitors of angiotensin converting enzyme, ARBs – angiotensin receptor blockers.
using BP dipping status as one of the BP diurnal variability parameters. A Cox proportional model was used for this goal. In order to compare continuous variables, a t-Student test or a UMann–Whitney test were used as appropriate. For categorical variables an x2 test was used. Continuous variables were reported as mean standard deviation, and categorical variables were reported as percentages, p < 0.05 was taken as the level of statistical significance. Statistical analyses were performed using STATISTICA version 10 (Tulsa, OK 74104, USA) and R version 3.0.1. The study protocol was approved by the Ethics Committee of the Medical University of Gdansk.
Results After considering the inclusion and exclusion criteria, 1345 out of 1908 consecutive patients admitted for elective coronary angiography were included in the study. We excluded 563 (28%) patients due to the following reasons: atrial fibrillation or atrial flutter (n = 138; 7%), congestive heart failure of NYHA class III or IV (n = 97; 5%), significant valvular heart disease or valvular heart disease qualifying the patient for cardiosurgery (n = 123; 6%), renal insufficiency with a creatinine level 2.0 mg/dL (n = 83; 4%), and other chronic diseases leading to limited life expectancy (n = 122;
Table 3 Monotherapy and combined therapy of hypertension in the studied groups. Total group n = 1345
Dippers n = 600
Monotherapy b-Blockers Calcium channel blockers ACE-I/ARB Diuretics a-Blockers Other medications
102 13 67 1 3 19
(8%) (1%) (5%) (0.1%) (0.3%) (1%)
42 6 30 0 0 12
(7%) (1%) (5%)
Two drug therapy b-Blocker + ACEI/ARB Calcium channel blockers + ACEI/ARB Diuretic + ACEI/ARB b-Blocker + Calcium channel blocker b-Blocker + Diuretic b-Blocker + a-blocker Calcium channel blocker + Diuretic ACE-I/ARB + a-blockers b-Blocker + other
538 60 19 21 13 6 1 3 20
(40%) (4%) (1%) (2%) (1%) (0.5%) (0.1%) (0.2%) (1%)
240 30 12 13 5 0 1 0 10
(40%) (5%) (2%) (2%) (1%)
205 114 27 6 6 18 3 1
(15%) (8%) (2%) (0.5%) (0.5%) (1%) (0.2%) (0.1%)
78 54 12 2 2 6 0 0
(13%) (9%) (2%) (0.3%) (0.3%) (1%)
(2%)
(0.2%) (2%)
Non dippers n = 745
p
60 7 37 1 3 7
(8%) (1%) (5%) (0.1%) (0.3%) (1%)
ns ns ns
298 30 7 8 8 6 0 3 10
(40%) (4%) (1%) (1%) (1%) (1%)
ns ns ns ns ns
127 60 15 4 4 12 3 1
(17%) (8%) (2%) (0.5%) (0.5%) (2%) (0.4%) (0.1%)
(0.4%) (1%)
ns
ns
Three drug therapy
b-Blocker + ACEI/ARB + Calcium channel blocker b-Blocker + ACEI/ARB + Diuretic b-Blocker + ACEI/ARB + a-blocker b-Blocker + Calcium channel blocker + Diuretic Calcium channel blockers + ACEI/ARB + a-blocker Calcium channel blockers + ACEI/ARB + Diuretic ACE-I/ARB + a-blockers + Diuretic b-Blocker + a-blocker + Diuretic More than three medications
81 (6%)
36 (6%)
45 (6%)
ns ns ns ns ns ns
ns
ASA – acetylosalicylic acid, lipid lowering drugs include statins and fibrates, ACE-I-inhibitors – inhibitors of angiotensin converting enzyme, ARBs – angiotensin receptor blockers.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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Table 4 Multiple logistic regression model for non-dipping status as response variable. Variable Intercept Age Diabetes No nighttime drug administration Office BP 140/90 mmHg
b coefficient 2.24 0.20 0.50 1.35 0.17
Standard error
Wald x2
p value
Odds ratio
95% CI
0.45 0.01 0.15 0.13 0.13
– 7.56 10.78 110.3 1.71
– <0.01 <0.01 <0.01 0.19
– 2.97 1.64 3.87 1.18
– 1.37–6.47 1.22–2.21 3.00–4.98 0.91–1.82
SBP – systolic blood pressure, CI – confidence interval.
Table 5 A Cox proportional hazards regression model showing the effect of age, diabetes, dipping status, clinic, daytime and nighttime BP thresholds and bedtime administration of antihypertensive drugs on the risk of all-cause mortality. Variable
b coefficient
Standard error
Wald x2
p value
Hazard ratio
95% CI
Age Diabetes Non dippers No nighttime drug administration Office BP 140/90 mmHg Daytime BP 135/85 mmHg Nighttime BP 120/70 mmHg
0.03 0.29 0.25 0.21 0.21 0.06 0.23
0.01 0.09 0.08 0.07 0.09 0.11 0.10
12.6 11.5 10.8 8.3 0.05 0.29 8.7
<0.01 <0.01 <0.03 <0.04 0.80 0.58 <0.03
1.03 1.79 1.17 1.13 1.04 1.12 1.25
1.01–1.05 1.28–2.52 1.02–1.47 1.01–1.45 0.73–1.50 0.74–1.70 1.03–1.91
SBP – systolic blood pressure, CI – confidence interval.
6%). There has been no change in antihypertensive pharmacotherapy for all included patients in the six month period before inclusion. Non-dipper patients accounted for 55% of the study population. Baseline characteristics of the total group as well as dippers and non-dippers are outlined in Table 1. The median follow-up period was 6.6 years (interquartile range 6.1–7.1 years). Qualitative analysis of medications did not reveal differences in the antihypertensive drugs used. Dippers and non-dippers differed in frequency of antihypertensive drugs administration i.e. in higher percentage of non-dippers antihypertensive drugs were administrated only in the morning but in lower percentage of non-dippers antihypertensive drugs were administrated twice or three times a day in comparison to dippers (Table 2). The studied groups did not differ in combined pharmacotherapy of hypertension (Table 3). A logistic regression model revealed the relationship between nonnighttime drug administration and non-dipping status (Table 4). A Cox proportional hazards regression model showed that nondipping status and non-nighttime pharmacotherapy of hypertension were connected with a higher risk of all-cause mortality in the studied population (Table 5). Discussion In this long-term single-centre study on patients with symptomatic CHD, we demonstrated that frequency of administration of antihypertensive drugs was different for non-dipper subjects and for dippers. Moreover, we revealed that non-dipping status was related to a lack of medications administration at bedtime. But the most important clinical implication is connected with the impact of non-dipping status and the lack of a nighttime medication administration regimen on mortality. O’Brien at al. first identified a group of hypertensive patients with blunted nighttime BP decrease and named them as nondippers [13]. Many clinical trials showed that this profile of BP is connected with a higher risk of CV events even in hypertensive patients with well-controlled BP [14]. Dauphinot et al. showed that in untreated hypertensive patients, non-dipping status was related to impaired autonomic nervous system activity [15]. But in treated hypertensive patients the impact of autonomic nervous system activity on circadian blood pressure profile might be distorted by antihypertensive medications. Hermida et al. revealed that in patients included in the Hygia Project circadian BP profile was
related to the treatment-time regimen of antihypertensive medications [16]. Our results confirmed these observations in the group of patients with established CHD. Moreover, instead of no differences between non-dippers and dippers in the quantity of drugs used and their combinations, we showed that non-dipping status was related to a less frequent bedtime administration of antihypertensive drugs. In our study, age, diabetes and non nighttime drug administration were determinants of non-dipping status. Among these variables, no nighttime drug administration increased the risk of non-dipping status by about four times. This seemingly obvious relationship is often overlooked in the determination of antihypertensive therapy. This fact may be the reason for sub-optimal BP control and the lack of decline in organ damage complications related to hypertension in recent years, despite increased intensity of therapy and the many new drugs approved for the therapy of hypertension [17,18]. It should be emphasized that the TTP ratio for all drugs used and their combinations was between 50% and 80%. Therefore, antihypertensive medications which were administrated only once a day did not provide total diurnal BP control. Although TTP was assessed for many antihypertensive drugs and their combinations, and was approved as a clinical parameter defining duration of action, it seems that physicians do not use it in clinical practice. In the context of our results, administration of antihypertensive drugs with a too low TTP could be one of the reasons for the high prevalence of non-dipping profile in the studied population, and might be one of the reasons for higher mortality in patients with blunted nighttime BP decrease. In the present study, there was a higher percentage of hypertensive patients with daytime BP in just over the target thresholds, but a lower percentage of patients with nighttime BP in over the target thresholds among dippers than non-dippers. However, there was no difference in the percentage of patients in over the target thresholds of clinic BP. This finding is important in determining pharmacological treatment on the basis of timeunspecified single clinic BP measurements. Hermida et al. revealed that an antihypertensive treatment regimen based on only clinic BP is both less effective and related to higher cardiovascular risk than using ABPM values when determining hypertension therapy in individual patients [19–21]. Our study has indirectly confirmed these findings in CHD patients with hypertension. We have
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009
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revealed that non-nighttime drug administration is related to higher risk in all-cause mortality. Moreover, neither overthreshold clinic BP nor over threshold daytime BP were significantly associated with risk of all-cause deaths. This finding might be explained by relatively satisfactory clinic and daytime BP control in the study group. But only over-nighttime BP threshold was related to higher all-cause mortality. On the other hand overdaytime BP threshold did not predict all-cause mortality in the study. Our results have important clinical implications. The use of information provided by ABPM, especially nighttime BP and diurnal BP variability, may lead to a greater reduction in mortality in CHD patients. In conclusion, our study confirmed that the non-dipping profile of CHD patients is related to the lack of administration of antihypertensive drugs with a relatively short TTP at bedtime. Moreover, pharmacotherapy based only on clinic BP measurements does not reduce mortality resulting from inappropriate BP diurnal rhythm. Wider use of ABPM devices by physicians might lead to a reduction in mortality caused by inappropriate BP diurnal rhythm. Conflict of interest No conflict of interest for all authors. There are no relationships with industry. Funding This study was supported by state committee for scientific research – KBN 2 P05B12727 from the Ministry of National Education in Poland. References [1] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care 2011;34:1270–6. [2] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol 2011;22:2313–21. [3] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int 2010;27:1629–51. [4] Boggia J, Li Y, Thijs L, Hansen TW, Kikuya M, Bjorklund-Bodegard K, et al. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 2007;370:1219–29.
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[5] Brotman DJ, Davidson MB, Boumitri M, Vidt DG. Impaired diurnal blood pressure variation and all-cause mortality. Am J Hypertens 2008;21:92–7. [6] Hermida RC, Ayala DE, Fernandez JR, Mojon A. Sleep-time blood pressure: prognostic value and relevance as a therapeutic target for cardiovascular risk reduction. Chronobiol Int 2013;30:68–86. [7] Hermida RC, Smolensky MH, Ayala DE, Portaluppi F. 2013 ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals. Chronobiol Int 2013;30:355–410. [8] Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213–25. [9] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J Am Coll Cardiol 2011;58:1165–73. [10] Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809–40. [11] Olsen TS, Langhorne P, Diener HC, Hennerici M, Ferro J, Sivenius J, et al. European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis 2003;16:311–37. [12] Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al. Management of acute myocardial infarction in patients presenting with STsegment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24: 28–66. [13] O’Brien E, Sheridan J, O’Malley K. Dippers and non-dippers. Lancet 1988;2:397. [14] Hermida RC, Ayala DE, Mojon A, Fernandez JR. Blunted sleep-time relative blood pressure decline increases cardiovascular risk independent of blood pressure level-the ‘‘normotensive non-dipper’’ paradox. Chronobiol Int 2013;30:87–98. [15] Dauphinot V, Gosse P, Kossovsky MP, Schott AM, Rouch I, Pichot V, et al. Autonomic nervous system activity is independently associated with the risk of shift in the non-dipper blood pressure pattern. Hypertens Res 2010;33:1032–7. [16] Hermida RC, Rios MT, Crespo JJ, Moya A, Dominguez-Sardina M, Otero A, et al. Treatment-time regimen of hypertension medications significantly affects ambulatory blood pressure and clinical characteristics of patients with resistant hypertension. Chronobiol Int 2013;30:192–206. [17] Catala-Lopez F, Sanfelix-Gimeno G, Garcia-Torres C, Ridao M, Peiro S. Control of arterial hypertension in Spain: a systematic review and meta-analysis of 76 epidemiological studies on 341 632 participants. J Hypertens 2012;30: 168–76. [18] Tocci G, Rosei EA, Ambrosioni E, Borghi C, Ferri C, Ferrucci A, et al. Blood pressure control in Italy: analysis of clinical data from 2005–2011 surveys on hypertension. J Hypertens 2012;30:1065–74. [19] Hermida RC, Ayala DE, Calvo C, Portaluppi F, Smolensky MH. Chronotherapy of hypertension: administration-time-dependent effects of treatment on the circadian pattern of blood pressure. Adv Drug Deliv Rev 2007;59:923–39. [20] Hermida RC, Ayala DE, Calvo C. Administration-time-dependent effects of antihypertensive treatment on the circadian pattern of blood pressure. Curr Opin Nephrol Hypertens 2005;14:453–9. [21] Portaluppi F, Hermida RC. Circadian rhythms in cardiac arrhythmias and opportunities for their chronotherapy. Adv Drug Deliv Rev 2007;59:940–51.
Please cite this article in press as: Sobiczewski W, et al. Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.009