Variations in Levels of Blood Pressure: Of Prognostic Value or Not?

Abstract

Related Article, p. 716 Related Article, p. 716 The usual clinical interpretation of blood pressure values relies on office (clinic) readings. A single clinic measurement of blood pressure predicts mortality sufficiently for actuarial purposes, but within-person fluctuations in blood pressure will tend to underestimate the true strength of association between “usual” blood pressure and cardiovascular outcomes.1Society of ActuariesBuild and Blood Pressure Study. Society of Actuaries, Chicago, IL1959Google Scholar A number of studies have reported U-shaped or reverse J-shaped relationships between blood pressure and mortality in patients treated by hemodialysis, with usual measurements obtained predialysis or postdialysis.2Port F.K. Hulbert-Shearon T.E. Wolfe R.A. et al.Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients.Am J Kidney Dis. 1999; 33: 507-517Abstract Full Text Full Text PDF PubMed Google Scholar, 3Zager P.G. Nikolic J. Brown R.H. et al.“U” Curve association of blood pressure and mortality in hemodialysis patients Medical Directors of Dialysis Clinic, Inc.Kidney Int. 1998; 54: 561-569Crossref PubMed Scopus (590) Google Scholar In this issue of the American Journal of Kidney Diseases, Brunelli et al4Brunelli S.M. Thadhani R.I. Lynch K.E. et al.Association between long-term blood pressure variability and mortality among incident hemodialysis patients.Am J Kidney Dis. 2008; 52: 716-726Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar report their findings of an association between long-term variations in levels of predialysis blood pressure and all-cause mortality in incident hemodialysis patients. In studies of the general population that make corrections for long-term variation in blood pressure by using repeated blood pressure measurements, more precise and less biased estimates of association can be made, and the strength of association is about 60% greater than reported in early studies using single measurements of blood pressure.5Lewington S. Clarke R. Qizilbash N. Peto R. Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (7449) Google Scholar, 6MacMahon S. Peto R. Cutler J. et al.Blood pressure, stroke, and coronary heart disease Part 1. Prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias.Lancet. 1990; 335: 765-774Abstract PubMed Scopus (3843) Google Scholar A more time-consuming method for measuring blood pressure entails the use of an ambulatory monitoring device. The 24-hour mean blood pressure levels thus obtained have predicted cardiovascular events even better than single or short-term mean clinic blood pressure measurements in individuals with untreated and treated hypertension.7Staessen J.A. Thijs L. Fagard R. et al.Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension Systolic Hypertension in Europe Trial Investigators.JAMA. 1999; 282: 539-546Crossref PubMed Scopus (1349) Google Scholar, 8Pickering T.G. Shimbo D. Haas D. Ambulatory blood-pressure monitoring.N Engl J Med. 2006; 354: 2368-2374Crossref PubMed Scopus (684) Google Scholar, 9Hansen T.W. Kikuya M. Thijs L. et al.Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: A meta-analysis of 7,030 individuals.J Hypertens. 2007; 25: 1554-1564Crossref PubMed Scopus (309) Google Scholar Comparisons have not been made with usual long-term blood pressures using repeated blood pressure measurements that frequently are available in routinely collected clinical data.10Hippisley-Cox J. Coupland C. Vinogradova Y. Robson J. May M. Brindle P. Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: Prospective open cohort study.BMJ. 2007; 335: 136Crossref PubMed Scopus (653) Google Scholar However, detailed assessments of ambulatory readings have further enhanced the understanding of the prognostic significance of short-term changes in blood pressure profiles. The key features of blood pressure pattern in healthy individuals include diurnal rhythm of blood pressure, differences in daytime and nighttime mean blood pressures, and blood pressure variability or minor fluctuations in amplitude around the mean blood pressure level. Although there has been inconsistency in the use of terms, most studies indicate that alteration in these patterns is associated with target-organ damage and cardiovascular disease. In healthy individuals, blood pressure dips in the initial hours of sleep and peaks in the early waking hours (morning surge). The difference between the 2 extremes is about 10% to 20%. A number of studies have shown that subjects with a less than 10% decrease in nocturnal blood pressure levels (nondippers) have an enhanced risk of cardiac, cerebral, kidney, and vascular damage.11Parati G. Pomidossi G. Albini F. Malaspina D. Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension.J Hypertens. 1987; 5: 93-98Crossref PubMed Scopus (956) Google Scholar Generally, individuals with hypertension or kidney disease or of African American descent show attenuated dipping and are observed to be at high risk. Restoration of a nocturnal dip in blood pressure has been associated with improvement in left ventricular ejection fraction.12Ko G.T. Chan H.C. Restoration of nocturnal dip in blood pressure is associated with improvement in left ventricular ejection fraction A 1-year clinical study comparing the effects of amlodipine and nifedipine retard on ambulatory blood pressure and left ventricular systolic function in Chinese hypertensive type 2 diabetic patients.Int J Cardiol. 2003; 89: 159-166Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar It is speculated that enhanced risk of cardiovascular disease in patients with chronic kidney disease may be mediated in part by abnormal diurnal rhythm. Epidemiological studies indicate that in the healthy population, daytime blood pressure levels are greater than nighttime levels. A reversal of this pattern with increased nighttime levels has been associated with adverse outcomes, including mortality.13Sega R. Facchetti R. Bombelli M. et al.Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: Follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) Study.Circulation. 2005; 111: 1777-1783Crossref PubMed Scopus (806) Google Scholar Interestingly, unlike daytime measurements, nighttime blood pressure levels do not correlate with office readings. Evidence suggests a greater benefit of a decrease in nighttime blood pressure on cardiovascular outcomes.14Svensson P. de Faire U. Sleight P. Yusuf S. Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: A HOPE Substudy.Hypertension. 2001; 38: E28-E32Crossref PubMed Google Scholar Thus, tracking nighttime blood pressure levels in response to antihypertensive agents may be particularly valuable for optimal benefit from therapy.15Minutolo R. Gabbai F.B. Borrelli S. et al.Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: An 8-week uncontrolled trial.Am J Kidney Dis. 2007; 50: 908-917Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar In patients with chronic kidney disease, increased nighttime systolic blood pressure has more strongly correlated with proteinuria than corresponding daytime values or office readings.16Agarwal R. Andersen M.J. Correlates of systolic hypertension in patients with chronic kidney disease.Hypertension. 2005; 46: 514-520Crossref PubMed Scopus (106) Google Scholar However, the direction of causality of this association and potential extension to faster progression to kidney failure remains to be established. Blood pressure variability is the beat-to-beat alteration in actual blood pressure around the predicted mean level. These continuous fluctuations in blood pressure levels are a result of complex interplay between external environmental stimuli and biological autonomic circulatory regulation. In clinical studies, blood pressure variability is generally measured by using an ambulatory device and calculated by means of the SD of the 24-hour average blood pressure value. These parameters have provided incremental prognostic information over conventional office blood pressure measurements.17Tatasciore A. Renda G. Zimarino M. et al.Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.Hypertension. 2007; 50: 325-332Crossref PubMed Scopus (218) Google Scholar Individuals with hypertension compared with those without hypertension have enhanced variability during both daytime and nighttime. It is speculated that wide swings in blood pressure have a mechanical impact on the vasculature. Evidence of the prognostic significance of blood pressure variability is accumulating, and results have been conflicting. Most studies have shown that 24-hour variability in systolic blood pressure is associated with cardiovascular complications in patients with treated hypertension, after accounting for risk attributable to increased levels of blood pressure. Excessive variability in daytime or awake systolic blood pressure has correlated with arthrosclerosis and end-organ damage (carotid intima-media thickness and left ventricular hypertrophy) in individuals in the general population and those with treated and untreated hypertension.17Tatasciore A. Renda G. Zimarino M. et al.Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.Hypertension. 2007; 50: 325-332Crossref PubMed Scopus (218) Google Scholar, 18Palatini P. Penzo M. Racioppa A. et al.Clinical relevance of nighttime blood pressure and of daytime blood pressure variability.Arch Intern Med. 1992; 152: 1855-1860Crossref PubMed Scopus (444) Google Scholar In the latter, this association was incremental to that caused by mean systolic blood pressure. However, similar relationships were not observed with nighttime variability, which probably reflects the concomitant beneficial impact of nocturnal dipping of blood pressure levels on cardiovascular outcomes. Consistent with this notion, revised computation of 24-hour variability after excluding a nocturnal decrease in blood pressure has been recommended by some.19Bilo G. Giglio A. Styczkiewicz K. et al.A new method for assessing 24-h blood pressure variability after excluding the contribution of nocturnal blood pressure fall.J Hypertens. 2007; 25: 2058-2066Crossref PubMed Scopus (164) Google Scholar At the same time, a number of studies, primarily of patients with treated hypertension, have failed to show a relationship between blood pressure variability and increased left ventricular mass.20Kristensen K.S. Hoegholm A. Bang L.E. Gustavsen P.H. Poulsen C.B. No impact of blood pressure variability on microalbuminuria and left ventricular geometry: Analysis of daytime variation, diurnal variation and 'white coat' effect.Blood Press Monit. 2001; 6: 125-131Crossref PubMed Scopus (31) Google Scholar It is possible that treatment with antihypertensive agents may have attenuated this risk, or there is no such association. This needs to be studied formally. Moreover, the reported associations are based on cross-sectional studies; therefore, causal relationships cannot be established. There has been considerable inconsistency in methods used to study variations in blood pressure, including blood pressure variability in patients on dialysis therapy.21Palatini P. Ambulatory blood pressure and cardiovascular risk in chronic kidney disease.Curr Hypertens Rep. 2008; 10: 119-126Crossref PubMed Scopus (15) Google Scholar Some have used ambulatory devices assessing a large number of values obtained every 15 to 30 minutes, whereas others have relied on single measurements obtained on predialysis days (generally thrice weekly) over months to years. The metrics used for defining blood pressure variability have also varied. Overall, these studies suggest that most patients on dialysis therapy are nondippers and are subject to marked blood pressure swings. Both increased interdialytic fluid gain and insufficient amount of dialysis enhance these fluctuations.22Narita I. Okada M. Omori S. et al.The circadian blood pressure rhythm in non-diabetic hemodialysis patients.Hypertens Res. 2001; 24: 111-117Crossref PubMed Scopus (19) Google Scholar Additional factors affecting variations in blood pressure in these patients are seasonal changes and arterial stiffness, which are captured better in long-term (weeks to months) studies.23Argiles A. Mourad G. Mion C. Seasonal changes in blood pressure in patients with end-stage renal disease treated with hemodialysis.N Engl J Med. 1998; 339: 1364-1370Crossref PubMed Scopus (112) Google Scholar The blunted decrease in nocturnal blood pressure in patients on dialysis therapy has been independently associated with increased left ventricular mass even after adjustment for mean blood pressure.24Rahman M. Griffin V. Heyka R. Hoit B. Diurnal variation of blood pressure; Reproducibility and association with left ventricular hypertrophy in hemodialysis patients.Blood Press Monit. 2005; 10: 25-32Crossref PubMed Scopus (49) Google Scholar Evidence also suggests that long-term blood pressure variability measured by means of either coefficient of variation or difference between maximum and minimum levels of predialysis systolic blood pressure are associated with mortality.25Tozawa M. Iseki K. Yoshi S. Fukiyama K. Blood pressure variability as an adverse prognostic risk factor in end-stage renal disease.Nephrol Dial Transplant. 1999; 14: 1976-1981Crossref PubMed Scopus (73) Google Scholar The findings of Brunelli et al4Brunelli S.M. Thadhani R.I. Lynch K.E. et al.Association between long-term blood pressure variability and mortality among incident hemodialysis patients.Am J Kidney Dis. 2008; 52: 716-726Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar are based on a large retrospective observational study of 6,961 incident hemodialysis patients. Predialysis blood pressure readings from days 91 to 180 were used. Raw blood pressure levels were transformed into various metrics. The average residual was computed as the difference between the observed and predicted blood pressure, with the latter based on a linear mixed-effects regression model of observed blood pressure over time. The model accounted for initial systolic blood pressure for the cohort, mean blood pressure slope for the cohort, and terms to account for differences between an individual's initial blood pressure and slope. The intercept represented initial blood pressure for each participant. The metric of residual to intercept ratio was used to account for greater fluctuations with higher mean blood pressure. Both systolic and diastolic blood pressure variability were associated with all-cause mortality during the subsequent 6 months of follow-up. Other expressions for variability, including coefficient of variation, did not have a stronger relationship. In addition, a U-shaped association was also observed between mean blood pressure and mortality.2Port F.K. Hulbert-Shearon T.E. Wolfe R.A. et al.Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients.Am J Kidney Dis. 1999; 33: 507-517Abstract Full Text Full Text PDF PubMed Google Scholar Unfortunately, information for interdialytic weight gain and adherence to antihypertensive medications was not obtained. It therefore is not possible to determine whether these modifiable behaviors contributed to the observed relationship of blood pressure variability with mortality. The reproducibility of blood pressure measurements and mathematical constructs of the models also need validation. Moreover, because 24-hour measurements of blood pressure were not obtained, comparative predictability with the office-based parameter of variability could not be assessed. Nevertheless, the advantage offered by ease of measurement in the routine dialysis setting is not trivial. If the findings of Brunelli et al4Brunelli S.M. Thadhani R.I. Lynch K.E. et al.Association between long-term blood pressure variability and mortality among incident hemodialysis patients.Am J Kidney Dis. 2008; 52: 716-726Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar are confirmed in other well-designed prospective studies, the robust association between long-term blood pressure variability based on office measurement of predialytic reading with mortality may be of high practical prognostic significance. Finally, as with all prognostic factors, randomized trials will be necessary to determine whether blood pressure variability based on predialysis readings is a therapeutic target. Support: None. Financial Disclosure: None. Association Between Long-term Blood Pressure Variability and Mortality Among Incident Hemodialysis PatientsAmerican Journal of Kidney DiseasesVol. 52Issue 4PreviewBlood pressure variability (BPV) is one putative risk factor for cardiovascular disease and mortality in hemodialysis patients. The purposes of this study are to identify a suitable metric of long-term BPV in this population and determine whether an association between BPV and all-cause mortality exists. Full-Text PDF