Heterogeneity of Prognostic Studies of 24-Hour Blood Pressure Variability: Systematic Review and Meta-Analysis

<div><p>In addition to mean blood pressure, blood pressure variability is hypothesized to have important prognostic value in evaluating cardiovascular risk. We aimed to assess the prognostic value of blood pressure variability within 24 hours. Using MEDLINE, EMBASE and Cochrane Library to April 2013, we conducted a systematic review of prospective studies of adults, with at least one year follow-up and any day, night or 24-hour blood pressure variability measure as a predictor of one or more of the following outcomes: all-cause mortality, cardiovascular mortality, all cardiovascular events, stroke and coronary heart disease. We examined how blood pressure variability is defined and how its prognostic use is reported. We analysed relative risks adjusted for covariates including the appropriate mean blood pressure and considered the potential for meta-analysis. Our analysis of methods included 24 studies and analysis of predictions included 16 studies. There were 36 different measures of blood pressure variability and 13 definitions of night- and day-time periods. Median follow-up was 5.5 years (interquartile range 4.2–7.0). Comparing measures of dispersion, coefficient of variation was less well researched than standard deviation. Night dipping based on percentage change was the most researched measure and the only measure for which data could be meaningfully pooled. Night dipping or lower night-time blood pressure was associated with lower risk of cardiovascular events. The interpretation and use in clinical practice of 24-hour blood pressure variability, as an important prognostic indicator of cardiovascular events, is hampered by insufficient evidence and divergent methodologies. We recommend greater standardisation of methods.</p></div

Numbers of studies reporting 24-hour blood pressure variability measures as a prognostic index of cardiovascular events.

<p>Providing continuous expressions of relative risk.</p><p>* Includes studies reporting relative risks/hazard ratios based on pooled data from other studies.</p><p>†Further data from an extra study could not be included as there was insufficient information to extract the data</p><p>‡Night-day ratio; SD—standard deviation, ARV—average real variability, CoV—coefficient of variation</p><p>Numbers of studies reporting 24-hour blood pressure variability measures as a prognostic index of cardiovascular events.</p

Associations of night-day ratio with cardiovascular outcomes.

<p>Relative risks:>1 increased risk;< 1 reduced risk. Pooled relative risk for all CV events, hypertensive population excluding de la Sierra 2012 only (did not control for treatment): 1.25 (1.00, 1.56), I-squared = 79.0%; excluding Verdecchia 1997 only:1.07 (0.99, 1.17), I-squared = 23.7%; excluding de la Sierra 2012 and Verdecchia 1997: 1.12 (0.98, 1.27), I-squared 33.6%.</p

Associations of systolic night dipping 1 with cardiovascular outcomes: non-dippers verses dippers, excluding risers and dippers.

<p>Relative risks:>1 increased risk;< 1 reduced risk. Pooled relative risk for all CV events, hypertensive populations, excluding Minutolo 2009 (non-dialysis chronic kidney disease): 1.61 (1.24, 2.10)</p

Associations of systolic night dipping 1 with cardiovascular outcomes: non-dippers verses dippers for all patients.

<p>Relative risks:>1 increased risk;< 1 reduced risk.</p

Associations of systolic night dipping 1 with cardiovascular outcomes: risers verses dippers.

<p>Relative risks:>1 increased risk;< 1 reduced risk. Pooled relative risk for all CV events, hypertensive populations, excluding Minutolo 2009 (non-dialysis chronic kidney disease): 1.81 (1.23, 2.66)</p

Studies included in systematic review.

<p>Abbreviations: <i>(excl)</i>—Excluded from analysis of relative risks; ARV—average real variability; CoV—coefficient or variation; CV—cardiovascular; MS—morning surge; SD—standard deviation.</p><p>*Relative risks/hazard ratios based on meta-analysis</p><p>^a Given for subgroups of patients so mean for all patients was estimated by calculating a weighted average</p><p>^b Provided separate relative risks for hypertensive and normotensive patients for night-day ratio (Boggia 2007, n = 3436 hypertensive, n = 4022 normtensive, CV events and all-cause mortality, systolic BP; Hansen 2006, n = 682 hypertensive, n = 1018 normotensive, CV events, systolic and diastolic BP)</p><p>Studies included in systematic review.</p

Study flow chart.

<p>Study flow chart.</p

Components of 24-hour BP variability measures.

<p>Based on 24 studies included in the review.</p><p>^astandard deviation / mean BP</p><p>^b average of absolute value of successive pairs of BP measurements</p><p>^c weighted average of day standard deviation and night standard deviation</p><p>^dpercentage nocturnal fall</p><p>^e difference of mean day BP and mean night BP</p><p>^f adjusted day-night difference, (mean day BP-mean night BP)/mean 24-hour BP</p><p>^gmean BP in 2 hours after awakening—mean BP in 2 hours preawakening</p><p>^hdifference between BP on rising and BP in 30 minutes before rising</p><p>ⁱdifference between mean BP in first hours after awakening and mean BP in last hour preawakening</p><p>^jdifference between mean BP in 3 hours after awakening and mean BP in 3 hours preawakening</p><p>^kdifference between mean BP in 2 hours after awakening and mean of the 3 BP readings centred on the lowest BP readings during sleep</p><p>^ldifference between mean BP in 2 hours after awakening and mean of all the BP readings during sleep</p><p>^mdifference between mean BP in 2 hours after awakening and lowest mean of 3 BP consecutive BP readings during the night</p><p>ⁿ≥20/15mmHg rise in first two BP readings from 7am compared to average night BP</p><p>Components of 24-hour BP variability measures.</p

Comparing predictive power of corresponding systolic and diastolic measures.

<p>G—general; M—mixed; H—hypertensive; HD—hypertensive, diabetes; SD—standard deviation; ARV—average real variability; RR—relative risk. Relative risks were scaled to the same increase except Pierdomenico 2009 (categorical expressions of relative risks). Sensitivity analysis (relative risks rescaled to 1 SD increase) are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126375#pone.0126375.s009" target="_blank">S5 Table</a>.</p><p>Comparing predictive power of corresponding systolic and diastolic measures.</p