- Email: [email protected]
Extended consensus on blood pressure variability beyond blood pressure for management of hypertension
Accepted Manuscript Extended Consensus on Blood Pressure Variability beyond Blood Pressure for Management of Hypertension Ram B. Singh, Krasimira Hristova, Geir Bjørklund, Jan Fedacko, Salvatore Chirumbolo, Daniel Pella PII:
S1933-1711(16)30589-7
DOI:
10.1016/j.jash.2016.11.005
Reference:
JASH 979
To appear in:
Journal of the American Society of Hypertension
Received Date: 3 September 2016 Revised Date:
10 November 2016
Accepted Date: 16 November 2016
Please cite this article as: Singh RB, Hristova K, Bjørklund G, Fedacko J, Chirumbolo S, Pella D, Extended Consensus on Blood Pressure Variability beyond Blood Pressure for Management of Hypertension, Journal of the American Society of Hypertension (2016), doi: 10.1016/j.jash.2016.11.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Extended Consensus on Blood Pressure Variability beyond Blood Pressure for Management of Hypertension Ram B. Singh1, Krasimira Hristova2, Geir Bjørklund3*, Jan Fedacko4, Salvatore Chirumbolo5,
RI PT
Daniel Pella4
1 - Halberg Hospital and Research Institute, Moradabad, India
2 - Division of Echocardiography Imaging, National Heart Hospital, Sofia, Bulgaria 3 - Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
SC
4 - Faculty of Medicine, Pavol Jozef Šafárik University, Kosice, Slovakia
M AN U
5 - Department of Medicine, University of Verona, Verona, Italy
*Corresponding Author: Geir Bjørklund
Council for Nutritional and Environmental Medicine Toften 24 8610 Mo i Rana, Norway
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Phone: +47 75130371 E-mail: [email protected]
AC C
management
EP
Key words: high blood pressure; blood pressure variability; hypertension; hypertension
1
ACCEPTED MANUSCRIPT 2
Since a long time, Franz Halberg (1919–2013) recommended that ambulatory monitoring of blood pressure (AMBP) may be useful in the risk evaluation of blood pressure variability (BPV) in patients with initially normal blood pressure (BP)1. It may even be used to indicate organ damage in individuals diagnosed with autonomic neuropathy, which is a condition that usually
RI PT
results in adverse effects on the autonomic control of the cardiovascular system1.
However, the auscultation of BP by following standardized protocols in the ambulatory medicine remains the golden standard2. Many attempts have been made to improve BP fluctuations, having an impact on cardiovascular function, sometimes with a positive outcome and
SC
encouraging results3,4. Current international guidelines recommend that the lower the systolic and diastolic blood pressure is, the better is the patient outcome5,6. Treating BPV may lead to
M AN U
positive and encouraging outcome of many cardiovascular-related disorders, principally hypertension-associated syndromes7, although it has to be distinguished a day-to-day home BPV or a visit-to-visit BPV in these outcomes8,9.
BPV should be properly and conceptually distinguished in its different terminology, where BV is usually associated with a beat-to-beat blood pressure, while the different night/day or circadian
TE D
parameters regarding BPV in general physiology and in the clinical approach (day vs. night, for example) are compulsively collected under the terminology of visit-to-visit BPV. In support of the current recommendations and guideline, there is a large body of evidence regarding the major role exerted of average BP values in determining the risk of cardiovascular
EP
disease (CVD), as cardiovascular damage and functional impairment are closely associated with elevated blood pressure levels10. Clinical randomized controlled trials (RCTs) about the role of
AC C
BPV in clinics seem to be scanty; few case reports can be reported11. Some trials were attempted to address recent incoming evidence regarding the ambulatory register of arterial stiffness, particularly useful in monitoring BPV12. An elevated blood pressure in conjunction with BPV may be a substantial contributor to morbidity and mortality, particularly in patients with metabolic syndrome and diabetes6,13-17. Furthermore, any impairment in the circadian rhythm may cause absence of nocturnal fall in BP, which is also caused by a reduced 24-h heart rate variability and an increased 24-h BPV14. The concept of as lower as the better systolic and diastolic BP, particularly among patients receiving drug therapy, has been recently reviewed. Several studies examined the effects of raised target 2
ACCEPTED MANUSCRIPT 3
BPs for high-risk patients, particularly for elderly patients and those subjects with or at high risk of coronary artery disease (CAD), for whom it has been proposed to wrap up the topic which does not appear to be absolutely correct18-20. The correct and reappraised relationship between BP and BPV in the monitoring and onset of cardiovascular disorders should, therefore, be
RI PT
reviewed. In this perspective, many authoritative guidelines should give their contribution, starting from the very recent Consensus Document on BPV21,22 on the basis of Rothwell’s observations23.
In a recent overview and meta-analysis on the issue, the effects of five major classes of BP
SC
lowering drugs on CVD outcomes were examined and compared with placebo20,24. Besides drugs, different attitudes in the dietary regimen, such as the so-called “dietary approach to stop
M AN U
hypertension” (DASH), dietary habits very poorly enriched of salts and hypertensive substances, are highly recommended25-27. The most relevant difference in the effectiveness of the various classes could correctly be estimated only by head-to-head comparisons of different categories of agents particularly if BP levels before and after therapy were examined by ABPM. However, in this new survey and meta-analysis, ABPM was out of the question in all the studies
TE D
included in the meta-analysis which identified 55 eligible randomized controlled trials for 68 two-drug comparisons. Random-effects model was used to find out risk ratios and their 95% confidence intervals. The results of this meta-analysis revealed that the effects of all the classes of drugs if their BP-lowering effect were equivalent and were not significantly different from
EP
most of the end points20,24.
The comparison of various categories of drugs revealed significant differences in outcome.
AC C
While diuretics were better suited in the prevention of heart failure, beta-blockers were not very efficient in preventing stroke, when compared to calcium channel blockers which were also more efficacious in reducing all-cause death, but less effective in preventing heart failure20. Patients with CAD showed better response with ACE inhibitors compared to angiotensin receptor blockers; both had lesser benefit in preventing stroke but more effective in preventing heart failure. No drug class was found to change the effectiveness of the level of risk on stratification of randomized, controlled trials according to total CVD risk. In this perspective, it would appear clear that it is not possible to formulate a fixed paradigm of drug choice, valuable for all the patients with hypertension, at least following the evidence 3
ACCEPTED MANUSCRIPT 4
reported to date. However, because of the many differences, specific choices in specific conditions, or preferable combinations of drugs may be suggested for treatment of a various group of patients as mentioned above19,20. Therefore, there is yet some uncertainty to select most among persons with and without diabetes or kidney diseas19-24,28,29.
RI PT
appropriate targets for systolic blood pressure to reduce morbidity and mortality due to CVD
In a recently reported randomized controlled trial, 9361 patients with a systolic blood pressure of 130 mm Hg or higher with an increased CVD risk, but excluding diabetes19. The target for the systolic blood pressure was less than 120 mm Hg (intensive treatment) or a threshold ≤ 140 mm
SC
Hg (standard treatment). The mean systolic blood pressure was 121.4 mm Hg in the intensivetreatment group and 136.2 mm Hg in the standard-treatment group after one year of follow-up12.
M AN U
AMBP blood pressure records were not available. There was a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001) after a median follow-up of 3.26 years. The intensive-treatment group had significantly lower all-cause mortality compared to the standard treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Also, complications such as
TE D
severe adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive treatment group than in the standard treatment group19.
EP
It is possible that among patients at high risk for CVD but without diabetes or metabolic syndrome, targeting a systolic BP of 120 mm Hg or lower, as compared with less than 140 mm Hg, may cause lower rates of fatal and non-fatal major CVD events, quite all causing deaths, at
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the cost of significantly higher rates of some adverse reactions. These adverse effects may be prevented by taking extra precautions in individual treatment and practice. A systematic review and meta-analysis including 123 studies with 613,815 participants was performed to clarify the influence of the baseline blood pressure, the presence of comorbidities, or drug class on the extent of benefit of reducing BPs30. The results revealed that every 10 mm Hg decline in systolic BP significantly reduced the risk of major CVD events (relative risk [RR] 0.80, 95% CI 0.77–0.83), CAD (0.83, 0.78–0.88), stroke (0.73, 0.68–0.77), and heart failure (0.72, 0.67–0.78), which, in the populations studied, led to a significant 13% reduction in all-
4
ACCEPTED MANUSCRIPT 5
cause mortality (0.87, 0.84–0.91), with a non-significant effect on renal failure. In trials with higher mean baseline systolic BP and trials with lower mean baseline systolic BP (all p <0·05), a comparable decline in risk frequency was reported. Thus, baseline disease history, except for diabetes and chronic kidney disease, showed no influence on the extent of risk reductions in
RI PT
major CVD events. However, for heart failure prevention, calcium channel blockers were less active while diuretics more than other drug classes. This meta-regression analyses showed relative risk reductions proportional to the magnitude of the BP reductions achieved.
In brief, it is possible to conclude that reduction in BP, causes a significant decrease in vascular
SC
risk across various baseline BP levels and co-morbidities. Reducing BP to systolic pressure less than 130 mm Hg and providing BP lowering treatment to individuals with a history of CVD,
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CAD, stroke, diabetes, heart failure, and chronic kidney disease appears to be of substantial benefit in providing cardiovascular protection24-44, although there is only a little opportunity to wrap-up the topic, as BP variabilities have not been considered in most of these trials. BPV may be particularly fundamental, besides AMBP, in resistant hypertension45,46. What is a true novelty for monitoring cardiovascular disorders and hypertension, is that recently
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reported studies showed that a visit-to-visit BPV is an independent risk for stroke. Although many further insights are needed, probably artery remodeling is associated with the variability, a
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EP
clinical sign which cannot be simply retrieved by ambulatory BP systolic and diastolic limits47.
5
ACCEPTED MANUSCRIPT 6
References 1. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report
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from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20.
2. Grim CE, Grim CM. Auscultatory BP: still the gold standard. J Am Soc Hypertens 2016;10:191-3.
3. Parati G, Schumacher H. Blood pressure variability over 24 h: prognostic implications and
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treatment perspectives. An assessment using the smoothness index with telmisartanamlodipine monotherapy and combination. Hypertens Res 2014;37:187-93.
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4. Hocht C. Blood pressure variability: prognostic value and therapeutic implications ISRN Hypertension 2013. doi:10.5402/2013/398485.
5. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31:1281–357.
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6. Halberg F, Powell D, Otsuka K, Watanabe Y, Beaty LA, Rosch P et al. Diagnosing vascular variability anomalies, not only MESOR-hypertension. Am J Physiol Heart Circ Physiol 2013;305: H279-294. doi:10.1152/ajpheart. 00212.2013. 7. Manning LS, Robinson TG. New Insights into Blood Pressure Control for Intracerebral
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Haemorrhage. Front Neurol Neurosci 2015;37:35-50. 8. Xu M, Wu Y, Wang H, Xu X, Zhao S, Zhang M, Jin H, Yan J, Wang B, Gong J, Lu X, Peng
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J, Dai Q. Effects of lercanidipine hydrochloride versus felodipine sustained-release on dayto-day home blood pressure variability. Curr Med Res Opin 2016;32(sup2):43-52. 9. Muntner P, Levitan EB. Visit-to-visit variability of blood pressure: current knowledge and future research directions. Blood Press Monit 2013;18:232-8. 10. Irigoyen MC, De Angelis K, Dos Santos F, Dartora DR, Rodrigues B, Consolim- Colombo FM. Hypertension, blood pressure variability, and target organ lesion. Curr Hypertens Rep 2016;18:31. doi:10.1007/s11906-016-0642-9. 11. Kim JS, Park S, Yan P, Jeffers BW, Cerezo C. Effect of inter-individual blood pressure variability on the progression of atherosclerosis in carotid and coronary arteries: a post hoc
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analysis of the NORMALISE and PREVENT studies. Eur Heart J Cardiovasc Pharmacother 2016. doi:10.1093/ehjcvp/pvw019. 12. Omboni S, Posokhov IN, Parati G, Avolio A, Rogoza AN, Kotovskaya YV, Mulè G, Muiesan ML, Orlova IA, Grigoricheva EA, Cardona Muñoz E, Zelveian PH, Pereira T,
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Peixoto Maldonado JM. Vascular Health Assessment of The Hypertensive Patients (VASOTENS) Registry: Study Protocol of an International, Web-Based Telemonitoring Registry for Ambulatory Blood Pressure and Arterial Stiffness. JMIR Res Protoc 2016;5:e137. doi:10.2196/resprot.5619.
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13. Cornelissen G, Otsuka K, Halberg F. Blood pressure and heart rate chronome mapping: a complement to the human genome initiative. In: Otsuka K, Cornélissen G, Halberg F. (Eds).
Publishing, 1993: 16-48.
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Chronocardiology and Chronomedicine: Humans in Time and Cosmos. Tokyo: Life Sciences
14. Singh RB, Hristova K, Pella D, Fedacko J, Kumar A, Chaves H et al. Extended consensus on guidelines for assessment of risk and management of hypertension: a scientific statement of the International College of Cardiology - thank you, Dr. Franz Halberg. World Heart J 2014;6:63-75.
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15. Rothwell PM. Limitations of the usual blood pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010;375:938-48. 16. Lee JY, Lee MS, Lee JS, Halber FE, Halberg J, Schwartzkoff O, Cornelissen G. A tribute to Franz Halberg. In Memorium. Hypertension 2015;66:1090-2.
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17. Cornelissen G, Halberg F, Bakken EE, Singh RB, Otsuka K, Tomlinson B et al. 100 or 30 years after Janeway or Bartter, Health watch helps avoid "flying blind". Biomed
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Pharmacother 2004;58(Suppl 1):S69-86. 18. Laurent S, Boutouyrie P. Blood pressure lowering trials: wrapping up the topic? Lancet 2016;387:923–4.
19. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16. 20. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses. J Hypertens 2015;33:1321-41.
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21. Zanchetti A. Consensus documents and challenges in hypertension research. J Hypertens 2016;34:1663-4. 22. Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, Kario K, Lurbe E, Manolis A, Mengden T, O'Brien E, Ohkubo T, Padfield P, Palatini P, Pickering TG, Redon J, Revera M,
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Ruilope LM, Shennan A, Staessen JA, Tisler A, Waeber B, Zanchetti A, Mancia G; ESH Working Group on Blood Pressure Monitoring. European Society of Hypertension practice guidelines for home blood pressure monitoring. J Hum Hypertens 2010;24:779-85.
23. Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlöf B, Poulter NR, Sever PS;
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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
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2010;9:469-80.
24. Thomopoulos C, Parati G, Zanchetti, A. Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs - overview and meta-analyses. J Hypertens 2015;33:195–211.
25. Rust P, Ekmekcioglu C. Impact of salt intake on the pathogenesis and treatment of hypertension. Adv Exp Med Biol 2016. doi:10.1007/5584_2016_147.
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26. de Paula TP, Steemburgo T, de Almeida JC, Dall'Alba V, Gross JL, de Azevedo MJ. The role of Dietary Approaches to Stop Hypertension (DASH) diet food groups in blood pressure in type 2 diabetes. Br J Nutr 2012;108:155-62. 27. Rankins J, Wortham J, Brown LL. Modifying soul food for the Dietary Approaches to Stop
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Hypertension diet (DASH) plan: implications for metabolic syndrome (DASH of Soul). Ethn Dis 2007;17(3 Suppl 4):S4-7-12.
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28. Emdin C, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes. JAMA 2015;313:603–15. 29. WHO. A global brief on hypertension. Geneva: World Health Organization, 2013. 30. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and metaanalysis. Lancet 2016;387:957–67. 31. Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 2016;387:435-43.
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32. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens 2014;32:3–15.
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33. Zanchetti A, Liu L, Mancia G, Parati G, Grassi G, Stramba-Badiale M et al. Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial. J Hypertens
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2014;32:1888-97.
34. Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S et al.
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Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy lifeyears lost, and age-specific associations in 1·25 million people. Lancet 2014;383:1899-911. 35. Wright JT Jr, Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med 2014;160:499–503.
36. Asayama K, Ohkubo T, Metoki H, Obara T, Inoue R, Kikuya M et al. Cardiovascular
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outcomes in the first trial of antihypertensive therapy guided by self-measured home blood pressure. Hypertens Res 2012;35:1102–10.
37. Ogihara T, Matsuoka H, Rakugi H. Practitioner's trial on the efficacy of antihypertensive treatment in elderly patients with hypertension II (PATE-hypertension II study) in Japan.
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Geriatr Gerontol Int 2011;11:414–21.
38. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr
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et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85.
39. Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314:52–60.
40. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204–13.
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41. Sundström J, Arima H, Jackson R, Turnbull F, Rahimi K, Chalmers J et al. Effects of blood pressure reduction in mild hypertension. Ann Intern Med 2015;162:184–91. 42. Rahimi K, MacMahon S. Blood pressure management in the 21st century: maximizing gains and minimizing waste. Circulation 2013;128:2283–5.
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43. Thomopoulos C, Parati G, Zanchetti, A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and meta-regression analyses of randomized trials. J Hypertens 2014;32:2285–95.
44. Blood Pressure Lowering Treatment Trialists' Collaboration, Ninomiya T, Perkovic V,
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Turnbull F, Neal B, Barzi F et al. Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled
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trials. BMJ 2013;347:f5680. doi:10.1136/bmj.f5680.
45. Doroszko A, Janus A, Szahidewicz-Krupska E, Mazur G, Derkacz A. Resistant hypertension. Adv Clin Exp Med 2016;25:173-83.
46. Grassi G, Bombelli M, Seravalle G, Brambilla G, Dell'oro R, Mancia G. Role of ambulatory blood pressure monitoring in resistant hypertension. Curr Hypertens Rep 2013;15:232-7 47. Nagai M, Dote K, Kato M, Sasaki S, Oda N, Kagawa E et al. Visit-to-visit blood pressure
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variability and classes of antihypertensive agents; associations with artery remodelling and
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the risk of stroke. Curr Pharm Des 2016;22:383-9
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Highlights Blood pressure variability (BPV) is an important diagnostic factor in cardiology
•
BPV plays a role in the pathogenesis of complications of hypertension
•
Treatment of BPV may give positive outcome in many cardiovascular-related disorders
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EP
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M AN U
SC
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•
S1933-1711(16)30589-7
DOI:
10.1016/j.jash.2016.11.005
Reference:
JASH 979
To appear in:
Journal of the American Society of Hypertension
Received Date: 3 September 2016 Revised Date:
10 November 2016
Accepted Date: 16 November 2016
Please cite this article as: Singh RB, Hristova K, Bjørklund G, Fedacko J, Chirumbolo S, Pella D, Extended Consensus on Blood Pressure Variability beyond Blood Pressure for Management of Hypertension, Journal of the American Society of Hypertension (2016), doi: 10.1016/j.jash.2016.11.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Extended Consensus on Blood Pressure Variability beyond Blood Pressure for Management of Hypertension Ram B. Singh1, Krasimira Hristova2, Geir Bjørklund3*, Jan Fedacko4, Salvatore Chirumbolo5,
RI PT
Daniel Pella4
1 - Halberg Hospital and Research Institute, Moradabad, India
2 - Division of Echocardiography Imaging, National Heart Hospital, Sofia, Bulgaria 3 - Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
SC
4 - Faculty of Medicine, Pavol Jozef Šafárik University, Kosice, Slovakia
M AN U
5 - Department of Medicine, University of Verona, Verona, Italy
*Corresponding Author: Geir Bjørklund
Council for Nutritional and Environmental Medicine Toften 24 8610 Mo i Rana, Norway
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Phone: +47 75130371 E-mail: [email protected]
AC C
management
EP
Key words: high blood pressure; blood pressure variability; hypertension; hypertension
1
ACCEPTED MANUSCRIPT 2
Since a long time, Franz Halberg (1919–2013) recommended that ambulatory monitoring of blood pressure (AMBP) may be useful in the risk evaluation of blood pressure variability (BPV) in patients with initially normal blood pressure (BP)1. It may even be used to indicate organ damage in individuals diagnosed with autonomic neuropathy, which is a condition that usually
RI PT
results in adverse effects on the autonomic control of the cardiovascular system1.
However, the auscultation of BP by following standardized protocols in the ambulatory medicine remains the golden standard2. Many attempts have been made to improve BP fluctuations, having an impact on cardiovascular function, sometimes with a positive outcome and
SC
encouraging results3,4. Current international guidelines recommend that the lower the systolic and diastolic blood pressure is, the better is the patient outcome5,6. Treating BPV may lead to
M AN U
positive and encouraging outcome of many cardiovascular-related disorders, principally hypertension-associated syndromes7, although it has to be distinguished a day-to-day home BPV or a visit-to-visit BPV in these outcomes8,9.
BPV should be properly and conceptually distinguished in its different terminology, where BV is usually associated with a beat-to-beat blood pressure, while the different night/day or circadian
TE D
parameters regarding BPV in general physiology and in the clinical approach (day vs. night, for example) are compulsively collected under the terminology of visit-to-visit BPV. In support of the current recommendations and guideline, there is a large body of evidence regarding the major role exerted of average BP values in determining the risk of cardiovascular
EP
disease (CVD), as cardiovascular damage and functional impairment are closely associated with elevated blood pressure levels10. Clinical randomized controlled trials (RCTs) about the role of
AC C
BPV in clinics seem to be scanty; few case reports can be reported11. Some trials were attempted to address recent incoming evidence regarding the ambulatory register of arterial stiffness, particularly useful in monitoring BPV12. An elevated blood pressure in conjunction with BPV may be a substantial contributor to morbidity and mortality, particularly in patients with metabolic syndrome and diabetes6,13-17. Furthermore, any impairment in the circadian rhythm may cause absence of nocturnal fall in BP, which is also caused by a reduced 24-h heart rate variability and an increased 24-h BPV14. The concept of as lower as the better systolic and diastolic BP, particularly among patients receiving drug therapy, has been recently reviewed. Several studies examined the effects of raised target 2
ACCEPTED MANUSCRIPT 3
BPs for high-risk patients, particularly for elderly patients and those subjects with or at high risk of coronary artery disease (CAD), for whom it has been proposed to wrap up the topic which does not appear to be absolutely correct18-20. The correct and reappraised relationship between BP and BPV in the monitoring and onset of cardiovascular disorders should, therefore, be
RI PT
reviewed. In this perspective, many authoritative guidelines should give their contribution, starting from the very recent Consensus Document on BPV21,22 on the basis of Rothwell’s observations23.
In a recent overview and meta-analysis on the issue, the effects of five major classes of BP
SC
lowering drugs on CVD outcomes were examined and compared with placebo20,24. Besides drugs, different attitudes in the dietary regimen, such as the so-called “dietary approach to stop
M AN U
hypertension” (DASH), dietary habits very poorly enriched of salts and hypertensive substances, are highly recommended25-27. The most relevant difference in the effectiveness of the various classes could correctly be estimated only by head-to-head comparisons of different categories of agents particularly if BP levels before and after therapy were examined by ABPM. However, in this new survey and meta-analysis, ABPM was out of the question in all the studies
TE D
included in the meta-analysis which identified 55 eligible randomized controlled trials for 68 two-drug comparisons. Random-effects model was used to find out risk ratios and their 95% confidence intervals. The results of this meta-analysis revealed that the effects of all the classes of drugs if their BP-lowering effect were equivalent and were not significantly different from
EP
most of the end points20,24.
The comparison of various categories of drugs revealed significant differences in outcome.
AC C
While diuretics were better suited in the prevention of heart failure, beta-blockers were not very efficient in preventing stroke, when compared to calcium channel blockers which were also more efficacious in reducing all-cause death, but less effective in preventing heart failure20. Patients with CAD showed better response with ACE inhibitors compared to angiotensin receptor blockers; both had lesser benefit in preventing stroke but more effective in preventing heart failure. No drug class was found to change the effectiveness of the level of risk on stratification of randomized, controlled trials according to total CVD risk. In this perspective, it would appear clear that it is not possible to formulate a fixed paradigm of drug choice, valuable for all the patients with hypertension, at least following the evidence 3
ACCEPTED MANUSCRIPT 4
reported to date. However, because of the many differences, specific choices in specific conditions, or preferable combinations of drugs may be suggested for treatment of a various group of patients as mentioned above19,20. Therefore, there is yet some uncertainty to select most among persons with and without diabetes or kidney diseas19-24,28,29.
RI PT
appropriate targets for systolic blood pressure to reduce morbidity and mortality due to CVD
In a recently reported randomized controlled trial, 9361 patients with a systolic blood pressure of 130 mm Hg or higher with an increased CVD risk, but excluding diabetes19. The target for the systolic blood pressure was less than 120 mm Hg (intensive treatment) or a threshold ≤ 140 mm
SC
Hg (standard treatment). The mean systolic blood pressure was 121.4 mm Hg in the intensivetreatment group and 136.2 mm Hg in the standard-treatment group after one year of follow-up12.
M AN U
AMBP blood pressure records were not available. There was a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001) after a median follow-up of 3.26 years. The intensive-treatment group had significantly lower all-cause mortality compared to the standard treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Also, complications such as
TE D
severe adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive treatment group than in the standard treatment group19.
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It is possible that among patients at high risk for CVD but without diabetes or metabolic syndrome, targeting a systolic BP of 120 mm Hg or lower, as compared with less than 140 mm Hg, may cause lower rates of fatal and non-fatal major CVD events, quite all causing deaths, at
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the cost of significantly higher rates of some adverse reactions. These adverse effects may be prevented by taking extra precautions in individual treatment and practice. A systematic review and meta-analysis including 123 studies with 613,815 participants was performed to clarify the influence of the baseline blood pressure, the presence of comorbidities, or drug class on the extent of benefit of reducing BPs30. The results revealed that every 10 mm Hg decline in systolic BP significantly reduced the risk of major CVD events (relative risk [RR] 0.80, 95% CI 0.77–0.83), CAD (0.83, 0.78–0.88), stroke (0.73, 0.68–0.77), and heart failure (0.72, 0.67–0.78), which, in the populations studied, led to a significant 13% reduction in all-
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cause mortality (0.87, 0.84–0.91), with a non-significant effect on renal failure. In trials with higher mean baseline systolic BP and trials with lower mean baseline systolic BP (all p <0·05), a comparable decline in risk frequency was reported. Thus, baseline disease history, except for diabetes and chronic kidney disease, showed no influence on the extent of risk reductions in
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major CVD events. However, for heart failure prevention, calcium channel blockers were less active while diuretics more than other drug classes. This meta-regression analyses showed relative risk reductions proportional to the magnitude of the BP reductions achieved.
In brief, it is possible to conclude that reduction in BP, causes a significant decrease in vascular
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risk across various baseline BP levels and co-morbidities. Reducing BP to systolic pressure less than 130 mm Hg and providing BP lowering treatment to individuals with a history of CVD,
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CAD, stroke, diabetes, heart failure, and chronic kidney disease appears to be of substantial benefit in providing cardiovascular protection24-44, although there is only a little opportunity to wrap-up the topic, as BP variabilities have not been considered in most of these trials. BPV may be particularly fundamental, besides AMBP, in resistant hypertension45,46. What is a true novelty for monitoring cardiovascular disorders and hypertension, is that recently
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reported studies showed that a visit-to-visit BPV is an independent risk for stroke. Although many further insights are needed, probably artery remodeling is associated with the variability, a
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clinical sign which cannot be simply retrieved by ambulatory BP systolic and diastolic limits47.
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Highlights Blood pressure variability (BPV) is an important diagnostic factor in cardiology
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BPV plays a role in the pathogenesis of complications of hypertension
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Treatment of BPV may give positive outcome in many cardiovascular-related disorders
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