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Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort StudyVisit-to-Visit Variability of BP on CVD and Mortality Outcomes

Paul Muntner, PhD; Jeff Whittle, MD; Amy I. Lynch, PhD; Lisandro D. Colantonio, MD; Lara M. Simpson, PhD; Paula T. Einhorn, MD; Emily B. Levitan, PhD; Paul K. Whelton, MD; William C. Cushman, MD; Gail T. Louis, RN; Barry R. Davis, MD, PhD; and Suzanne Oparil, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 28 July 2015.


From University of Alabama at Birmingham, Birmingham, Alabama; Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin; University of Texas School of Public Health, Houston, Texas; National Heart, Lung, and Blood Institute, Bethesda, Maryland; Tulane University, New Orleans, Louisiana; and Veterans Affairs Medical Center, Memphis, Tennessee.

This study was presented as a poster at the 2014 American Society of Hypertension meeting on 19 May 2014 in New York, New York.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial Support: By the National Heart, Lung, and Blood Institute of the National Institutes of Health (contracts NO1-HC-35130 and HHSN268201100036C and award R01 HL110993); further, the ALLHAT investigators acknowledge study medications contributed by Pfizer (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin) and financial support from Pfizer.

Disclosures: Dr. Muntner reports grants from the National Institutes of Health during the conduct of the study and grants and personal fees from Amgen outside the submitted work; Dr. Simpson reports grants from University of Alabama at Birmingham during the conduct of the study; Dr. Levitan reports grants from Amgen and GlaxoSmithKline (pending [at the time of manuscript acceptance]) and personal fees from Robinson Calcagnie Robinson Shapiro Davis outside of the submitted work; Dr. Cushman reports grants from Eli Lilly and Company and Merck and uncompensated work (member of steering committee and consultancy) with Takeda; Dr. Davis reports grants from University of Alabama at Birmingham during the conduct of the study; and Dr. Oparil reports work as a consultant for AstraZeneca, Bayer, and Daiichi Sankyo and has received institutional research funding from Novartis, Medtronic (Ardian), Bayer HealthCare Pharmaceuticals, AstraZeneca (Duke University), and Merck. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-2803.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol: Available from Dr. Muntner (e-mail, pmuntner@uab.edu). Statistical code: Not available. Data set: Available at https://biolincc.nhlbi.nih.gov/studies/allhat.

Requests for Single Reprints: Paul Muntner, PhD, University of Alabama at Birmingham, 1700 University Boulevard, Suite 450, Birmingham, AL 35294; e-mail, pmuntner@uab.edu.

Current Author Addresses: Dr. Muntner: University of Alabama at Birmingham, 1700 University Boulevard, Suite 450, Birmingham, AL 35294.

Dr. Whittle: Clement J. Zablocki Veterans Affairs Medical Center, Mailstop 00 (PC), 5000 West National Avenue, Milwaukee, WI 53295.

Dr. Lynch: University of Alabama at Birmingham, 1665 University Boulevard, Suite 220, Birmingham, AL 35294.

Dr. Colantonio: Department of Epidemiology, University of Alabama at Birmingham, 1700 University Boulevard, Suite 446, Birmingham, AL 35294.

Drs. Simpson and Davis: University of Texas School of Public Health, 1200 Hermann Pressler Street, Houston, TX 77030.

Dr. Einhorn: Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, 2 Rockledge Centre, Room 10222, 6701 Rockledge Drive, MSC 7936, Bethesda, MD 20892.

Dr. Levitan: University of Alabama at Birmingham, 1700 University Boulevard, Suite 452, Birmingham, AL 35294.

Dr. Whelton: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Room 2018, New Orleans, LA 70112.

Dr. Cushman: Memphis Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104.

Ms. Louis: Tulane University, Office of Research, 1440 Canal Street, Suite 2400, TW-5, New Orleans, LA 70118.

Dr. Oparil: University of Alabama at Birmingham, 703 19th Street South, ZRB 1034, Birmingham, AL 35294.

Author Contributions: Conception and design: P. Muntner, J. Whittle, P.T. Einhorn, W.C. Cushman.

Analysis and interpretation of the data: P. Muntner, J. Whittle, A.I. Lynch, L.D. Colantonio, L.M. Simpson, P.T. Einhorn, E.B. Levitan, P.K. Whelton, W.C. Cushman, B.R. Davis, S. Oparil.

Drafting of the article: P. Muntner, L.M. Simpson, P.T. Einhorn, P.K. Whelton, G.T. Louis, S. Oparil.

Critical revision of the article for important intellectual content: J. Whittle, L.D. Colantonio, L.M. Simpson, P.T. Einhorn, E.B. Levitan, P.K. Whelton, W.C. Cushman, G.T. Louis, B.R. Davis, S. Oparil.

Final approval of the article: P. Muntner, J. Whittle, L.D. Colantonio, L.M. Simpson, P.T. Einhorn, E.B. Levitan, P.K. Whelton, W.C. Cushman, G.T. Louis, B.R. Davis, S. Oparil.

Provision of study materials or patients: J. Whittle, L.M. Simpson, W.C. Cushman, B.R. Davis.

Statistical expertise: P. Muntner, L.D. Colantonio, L.M. Simpson, E.B. Levitan, B.R. Davis.

Obtaining of funding: P. Muntner, J. Whittle.

Administrative, technical, or logistic support: L.D. Colantonio, L.M. Simpson, B.R. Davis.

Collection and assembly of data: J. Whittle, L.M. Simpson, P.K. Whelton, W.C. Cushman, B.R. Davis, S. Oparil.


Ann Intern Med. 2015;163(5):329-338. doi:10.7326/M14-2803
Text Size: A A A

Background: Variability of blood pressure (BP) across outpatient visits is frequently dismissed as random fluctuation around a patient's underlying BP.

Objective: To examine the association of visit-to-visit variability (VVV) of systolic BP (SBP) and diastolic BP with cardiovascular disease (CVD) and mortality outcomes.

Design: Prospective cohort study.

Setting: Post hoc analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).

Participants: 25 814 ALLHAT participants.

Measurements: The VVV of SBP was defined as the SD across SBP measurements obtained at 7 visits conducted from 6 to 28 months after ALLHAT enrollment. Participants without CVD events during the first 28 months of follow-up were followed from the 28-month visit through the end of active ALLHAT follow-up. Outcomes included fatal coronary heart disease (CHD) or nonfatal myocardial infarction, all-cause mortality, stroke, and heart failure.

Results: During follow-up, 1194 fatal CHD or nonfatal MI events, 1948 deaths, 606 strokes, and 921 heart failure events occurred. After multivariable adjustment, including for mean SBP, the hazard ratio comparing participants in the highest versus lowest quintile of SD of SBP (≥14.4 mm Hg vs. <6.5 mm Hg) was 1.30 (95% CI, 1.06 to 1.59) for fatal CHD or nonfatal MI, 1.58 (CI, 1.32 to 1.90) for all-cause mortality, 1.46 (CI, 1.06 to 2.01) for stroke, and 1.25 (CI, 0.97 to 1.61) for heart failure. Higher VVV of diastolic BP was also associated with CVD events and mortality.

Limitation: Long-term outcomes were not available.

Conclusion: Higher VVV of SBP is associated with an increased risk for CVD and mortality. Future studies should examine whether reducing VVV of BP lowers this risk.

Primary Funding Source: National Institutes of Health.

Figures

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Figure 1.

Study design evaluating the association between VVV of BP and cardiovascular outcomes and all-cause mortality in ALLHAT.

ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; VVV = visit-to-visit variability.

* Participants were followed for a mean of 2.7 to 2.9 y (maximum, 5.7 y) depending on the outcome after assessment of VVV of BP.

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Appendix Figure.

Formulas used to calculate VVV of BP metrics.

ARV = average real variability; BP = blood pressure; SDIM = SD independent of the mean; VVV = visit-to-visit variability.

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Figure 2.

Cumulative incidence of the 4 outcomes, by quintile of intraindividual SD of SBP.

CHD = coronary heart disease; MI = myocardial infarction; SBP = systolic blood pressure.

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Figure 3.

Hazard ratios of the 4 outcomes associated with the highest versus lowest quintile of intraindividual SD across ALLHAT follow-up visits conducted 6 to 28 months after baseline in selected subgroups.

Data were adjusted for age, sex, race/ethnicity, region of residence, randomization assignment, smoking status, body mass index, estimated glomerular filtration rate, diabetes, total cholesterol level, history of MI or stroke, history of coronary revascularization, atrial fibrillation by electrocardiography, history of other atherosclerotic CVD, major ST depression or T-wave inversion, LVH, low high-density lipoprotein cholesterol level, aspirin use, use of BP medications before study randomization, statin use, pulse pressure, medication adherence, antihypertensive medication classes being received, changes in antihypertensive medication classes being received, and mean systolic BP. Further, BP control was defined as systolic or diastolic BP less than 140/90 mm Hg. All interaction P values were greater than 0.10 for each subgroup and outcome except when comparing LVH on all-cause mortality (interaction P = 0.016) and lisinopril versus chlorthalidone on stroke (interaction P = 0.083). ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; BP = blood pressure; CHD = coronary heart disease; CVD = cardiovascular disease; HR = hazard ratio; LVH = left ventricular hypertrophy; MI = myocardial infarction.

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Figure 4.

Hazard ratios of the 4 outcomes associated with intraindividual SD across ALLHAT follow-up visits conducted 6 to 28 months after baseline by using restricted quadratic splines.

The solid black line in each figure represents the HR, and the green shaded area represents the 95% CI. The histogram represents the distribution of SD of SBP in the ALLHAT population. Data were adjusted for age, sex, race/ethnicity, region of residence, randomization assignment, smoking status, body mass index, estimated glomerular filtration rate, diabetes, total cholesterol level, history of MI or stroke, history of coronary revascularization, atrial fibrillation by electrocardiography, history of other atherosclerotic cardiovascular disease, major ST depression or T-wave inversion, left ventricular hypertrophy, low high-density lipoprotein cholesterol level, aspirin use, use of blood pressure medications before study randomization, statin use, pulse pressure, medication adherence, antihypertensive medication classes being received changes in antihypertensive medication classes being received and mean SBP. ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CHD = coronary heart disease; HR = hazard ratio; MI = myocardial infarction; SBP = systolic blood pressure.

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Comment
Posted on October 21, 2015
Marcin Wirtwein, Wojciech Sobiczewski
Medical University of Gdansk
Conflict of Interest: None Declared
In the previous issue of Annals of Internal Medicine, a very interesting article was published concerning the relationship between visit-to-visit variability (VVV) of blood pressure and cardiovascular (CV) disease and mortality outcomes. Muntner et al. performed a secondary data analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study. The authors included a total of 25814 subjects in the analysis. Standard deviation (SD) was used as a parameter of blood pressure (BP) variability. Data analysis confirmed that higher VVV of systolic BP (SBP) is related to an increased risk of CV disease and mortality [1]. Despite the very important clinical implications in BP control related to the findings of this study, some questions arise, which we believe need explanation.
Muntner et al. analyzed BP values from the ALLHAT study choosing to begin the assessment six month follow-up visit in order to avoid an initial reduction of BP due to early medication titration. But according to the ALLHAT study protocol antihypertensive drugs dosage titration was scheduled (if needed) at 6, 9 and 12 months after randomization [2]. In our opinion, titration of antihypertensive drugs dosage may influence VVV. However in the present article, model 3 was adjusted for an antihypertensive medication regimen, all of which occurred during the assessment period (months 6 to 28 of follow-up), but was not adjusted for antihypertensive drugs dosage titration [1].
The undoubted advantage of the findings of this article is to confirm SBP VVV is related to CV risk. VVV was calculated as SDs from office BP values measured during scheduled visits in the ALLHAT study. Although this method takes into account variability in the scale of months, it does not take into consideration nocturnal BP variability. Some clinical trials confirmed that daytime-nighttime BP variability is a strong predictor of CV outcomes [3]. In their assessment of VVV, Muntner et al. did not take into account the time when the drugs were taken. If the time was variable in the follow-up period, it could have influenced BP values and VVV. But on the other hand, even if the drugs were administrated at the same time, measurements performed in the different parts of day might have influenced VVV.
About 35% of Afro-Americans (in each treatment group) were included in the ALLHAT study. This study confirmed that the treatment of hypertension may depend on race. In the black racial subgroup about 4 mmHg lower SBP values were observed in the diuretic treatment subgroup than in ACE-I subgroup. Similarly, the diuretic produced a higher SBP reduction (about 3 mmHg) than ACE-I in the patients ≥65 years of age. But amlodipine produced a higher reduction in DBP values than lisinopril. In the study by Muntner et al. there was no performed analysis of VVV in the particular race subgroups and treatment subgroups. Some clinical trials have confirmed that there is superiority of one class of antihypertensive drugs over others in reducing BP variability [4]. Moreover, results from the ALLHAT study confirmed the superiority of some antihypertensive drugs over others in reducing CV risk in hypertensive patients [5]. Therefore, maybe certain drug classes or even particular drugs as well as their combinations intensify or impair the effect of VVV on CV risk.
Muntner et al. studied four outcomes: fatal coronary heart disease or nonfatal myocardial infarction, all-cause mortality, stroke and heart failure [1]. Patients with CV risk factors other than hypertension were included in the study [2]. Some of them had several CV risk factors that increased disproportionately the total CV risk of a particular patient. In the analysis by Muntner et al., nested models included variables being risk factors. In our opinion, adjustment for cumulative CV risk (e.g. expressed as CV score) may better reflect independent VVV influence on CV outcomes.
In the ALLHAT study over 30% of patients were treated with aspirin [2]. Models constructed by Muntner et al. included the use of aspirin only but not the time of aspirin administration. Some previously performed studies confirmed that the time of aspirin use is related to a different BP reduction [6].
The article by Muntner et al. undoubtedly provides important clinical implications concerning the relationship between VVV and CV events and mortality. We are convinced that VVV should be taken into account in cardiovascular risk stratification in hypertensive patients, and that this may further improve treatment results in this group of patients.

1. Muntner, P., et al., Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort Study. Ann Intern Med, 2015. 163(5): p. 329-38.
2. Davis, B.R., et al., Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens, 1996. 9(4 Pt 1): p. 342-60.
3. Sobiczewski, W., et al., Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status. Pharmacol Rep, 2014. 66(3): p. 448-52.
4. Webb, A.J., et al., Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet, 2010. 375(9718): p. 906-15.
5. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-
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Summary for Patients

Variation in Blood Pressure Readings and the Risk for Cardiovascular Disease

The full report is titled “Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality. A Cohort Study.” It is in the 1 September 2015 issue of Annals of Internal Medicine (volume 163, pages 329-338). The authors are P. Muntner, J. Whittle, A.I. Lynch, L.D. Colantonio, L.M. Simpson, P.T. Einhorn, E.B. Levitan, P.K. Whelton, W.C. Cushman, G.T. Louis, B.R. Davis, and S. Oparil.

This article was published online first at www.annals.org on 28 July 2015.

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