Association Between Antihypertensive Medication Adherence and Visit‐to‐Visit Variability of Blood Pressure

It has been hypothesized that high visit‐to‐visit variability (VVV) of systolic blood pressure (SBP) may be the result of poor antihypertensive medication adherence. The authors studied this association using data from 1391 individuals taking antihypertensive medication selected from a large managed care organization. The 8‐item Morisky Medication Adherence Scale, administered during 3 annual surveys, captured self‐report adherence, with scores <6, 6 to <8, and 8 representing low, medium. and high adherence, respectively. The mean (standard deviation [SD]) for SD of SBP across study visits was 12.9 (4.4), 13.5 (4.8), and 14.1 (4.5) mm Hg in participants with high, medium, and low self‐reported adherence, respectively. After multivariable adjustment and compared with those with high self‐report adherence, SD of SBP was 0.60 (95% confidence interval, 0.13–1.07) and 1.08 (95% confidence interval, 0.29–1.87) mm Hg higher among participants with medium and low self‐report adherence, respectively. Results were consistent when pharmacy fill was used to define adherence. These data suggest that low antihypertensive medication adherence explains only a small proportion of VVV of SBP. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.     

Visit‐to‐Visit Blood Pressure Variability and Cardiovascular Death in the Systolic Hypertension in the Elderly Program

Most studies of an association of visit‐to‐visit variability of blood pressure with increased risk of future adverse cardiovascular events are of short duration and rarely include a placebo group. Using data from the double‐blind, placebo‐controlled Systolic Hypertension in the Elderly Program, the authors examined mortality from cardiovascular causes up to 17 years of follow‐up using the National Death Index. Visit‐to‐visit blood pressure variability was associated with cardiovascular death after adjustment for sex, age, serum creatinine, diabetes, body mass index, smoking status, left ventricular failure, and high‐density lipoprotein cholesterol. The relationship was significantly stronger in the active treatment group compared with the placebo group. Although this could be the result of an effect of the medications used unrelated to visit‐to‐visit variability, the data are compatible with the hypothesis that inconsistent adherence leading to missing active medication doses may be an additional explanation for the relationship of visit‐to‐visit variability with cardiovascular death.     

Visit‐to‐Visit Variability of Blood Pressure and Renal Function Decline in Patients With Diabetic Chronic Kidney Disease

The authors previously reported that the visit‐to‐visit variability of blood pressure is correlated with renal function decline in nondiabetic chronic kidney disease. Little is known about the association between visit‐to‐visit variability and renal function decline in patients with diabetic chronic kidney disease. The authors retrospectively studied 69 patients with diabetic chronic kidney disease stage 3a, 3b, or 4. The standard deviation and coefficient of variation of blood pressure in 12 consecutive visits were defined as visit‐to‐visit variability of blood pressure. The median observation period was 32 months. In univariate correlation, the standard deviation and coefficient of variation of blood pressure were not significantly associated with the slope of estimated glomerular filtration rate. There was no significant association between the visit‐to‐visit variability of blood pressure and renal function decline in patients with diabetic chronic kidney disease, in contrast with our previous study of nondiabetic patients with chronic kidney disease.     

Prognostic Significance of Visit‐to‐Visit Systolic Blood Pressure Variability: A Meta‐Analysis of 77,299 Patients

In recent clinical investigations, visit‐to‐visit systolic blood pressure (SBP) variability was proven as a predictor of cardiovascular events and all‐cause mortality. However, inconsistent results exist in this association. A meta‐analysis of 13 prospective studies was conducted to evaluate the prognostic value of visit‐to‐visit SBP variability by different parameters in 77,299 patients with a mean follow‐up of 6.3 years. The pooled age‐ and mean SBP‐adjusted hazard ratios (HRs) for all‐cause mortality were 1.03 (95% confidence interval [CI], 1.02–1.04; P<.001) per 1‐mm Hg increase in SBP standard deviation (SD) and 1.04 (1.02–1.06, P<.001) per 1% in SBP coefficient of variation, and the corresponding values of cardiovascular mortality were 1.10 (1.02–1.17, P<.001) and 1.01 (0.99–1.03, P=.32), respectively. Moreover, a 1‐mm Hg increase in SD was significantly associated with stroke, with an HR of 1.02 (1.01–1.03, P<.001). Visit‐to‐visit SBP variability, independent of age and mean SBP, is a predictor of cardiovascular and all‐cause mortality and stroke.     

Effect of Chlorthalidone,Amlodipine, and Lisinopril on Visit‐to‐Visit Variability of Blood Pressure: Results From the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial

Few randomized trials have compared visit‐to‐visit variability (VVV) of systolic blood pressure (SBP) across drug classes. The authors compared VVV of SBP among 24,004 participants randomized to chlorthalidone, amlodipine, or lisinopril in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of SBP was calculated across 5 to 7 visits occurring 6 to 28 months following randomization. The standard deviation (SD) of SBP was 10.6 (SD=5.0), 10.5 (SD=4.9), and 12.2 (SD=5.8) for participants randomized to chlorthalidone, amlodipine, and lisinopril, respectively. After multivariable adjustment including mean SBP across visits and compared with participants randomized to chlorthalidone, participants randomized to amlodipine had a 0.36 (standard error [SE]: 0.07) lower SD of SBP and participants randomized to lisinopril had a 0.77 (SE=0.08) higher SD of SBP. Results were consistent using other VVV of SBP metrics. These data suggest chlorthalidone and amlodipine are associated with lower VVV of SBP than lisinopril.     

Medication Class Effects on Visit‐to‐Visit Variability of Blood Pressure Measurements: Analysis of Electronic Health Record Data in the “Real World”

Blood pressure (BP) visit‐to‐visit variability (VVV) influences the risk of vascular events and mortality. Research has suggested that antihypertensive medication classes may differentially impact VVV. This study evaluated whether antihypertensive medication class differentially impacted BP VVV among hypertensive individuals in a clinical, “real‐world” setting as well as the association between VVV and patient characteristics. Clinical observational data were extracted for adults (mean age, 63; 56% female, 86% Caucasian) with hypertension from the Mercy EpicCare EHR‐Derived Database (MEDD) (n=183,374) who had at least 4 outpatient visits with BP readings. A multilevel mixed model for change over time estimated between‐ and within‐subject effects on the absolute real VVV of systolic BP. Diuretics significantly lowered VVV (β=−0.32[−0.39 to−0.25]) and α‐/β‐blockers resulted in the highest VVV (β=0.89 [0.77–1.00]). Being older, female, and having a higher systolic BP and certain comorbid conditions significantly raised VVV (P<.001). The findings from the MEDD were consistent in general with other research on BP VVV. However, the magnitude of effect of antihypertensive medication class and patient characteristics was relatively low (<10% of the BP VVV variance for any one variable). More research is needed to evaluate the extent to which the class of antihypertensive medication class impacts BP VVV in the outpatient setting.

Long‐term poorly controlled blood pressure (BP) in hypertensive patients is associated with increased cardiovascular, renal, and cerebrovascular morbidity and mortality.¹, ², ³ Although the individual''s systolic BP level is considered of primary importance in assessing risk of vascular events, it is possible that other BP parameters might also be influential. One such parameter that has been proposed is BP visit‐to‐visit variability (VVV).⁴, ⁵, ⁶, ⁷ Although BP VVV has at times been considered a nuisance variable,⁸, ⁹, ¹⁰, ¹¹ there is burgeoning literature on the topic.⁶, ⁷, ¹² Rothwell and colleagues reported that in two large trials (United Kingdom Transient Ischaemic Attack [UK‐TIA aspirin] trial and the Anglo‐Scandinavian Cardiac Outcomes Trial‐Blood Pressure Lowering Arm [ASCOT‐BPLA]) systolic BP (SBP) VVV was found to be predictive of stroke and coronary events, including mortality (and was independent of mean SBP).⁶, ¹³ Munter and colleagues found that higher SBP VVV is associated with an increased risk of negative cardiovascular outcomes and end‐organ damage.⁷ BP VVV has been previously shown to be associated with adverse outcomes such as mortality and cardiovascular events,¹², ¹⁴ yet there remains a gap to demonstrate what factors may explain higher levels of VVV.Antihypertensive medications may have class‐specific effects on BP VVV.¹³, ¹⁵ A recent meta‐analysis considering VVV across multiple randomized trials reported that some antihypertensive classes (calcium channel blockers, diuretics) decrease VVV, while others (angiotensin‐converting enzyme inhibitors, β‐blockers) increase VVV.¹⁵ Within the ASCOT‐BPLA trial it was reported that using a calcium channel blocker resulted in a 24% decrease in cardiovascular mortality and a 23% decrease in stroke compared with β‐blocker therapy.¹⁶ In at least one study, VVV was associated with being older and female and a predictor of myocardial infarction.⁶ Given the potential impact of BP VVV on vascular events, it is important to evaluate whether certain patient characteristics are associated with BP VVV. Due to the evolving understanding of BP VVV on clinical outcomes, more work needs to be conducted to evaluate whether BP VVV is differentially influenced by the various classes of antihypertensive medications as well as patient characteristics.In order to appreciate these relationships in a “real‐world” setting, it would be beneficial to examine a clinical electronic health record (EHR)–derived database. The current study had two main objectives. The first objective was to investigate whether antihypertensive class differentially affected VVV among individuals in an EHR‐derived database, while the second objective was to investigate the effect of patient characteristics on VVV.     

Visit‐to‐visit variability in blood pressure and Alzheimer's disease

Alzheimer's disease is the most common type of dementia and one of the leading sources of disability and dependency in the elderly. Given the limited treatment options, understanding the role of modifiable risk factors implied in the disease pathogenesis is a worthwhile endeavor to limit its global burden. Recently, the variability of blood pressure has been suggested to be a significant determinant of brain alterations and a potential therapeutic target. The aim of this article is to review the clinical evidence on the association between visit‐to‐visit blood pressure variability and Alzheimer's disease, highlight the underlying mechanisms, and suggest future implications.     

Ambulatory Blood Pressure,Blood Pressure Variability and Antihypertensive Treatment

Ambulatory blood pressure monitoring is frequently employed in the clinical practice to improve the diagnosis of hypertension and the appropriateness of the decision regarding initiation of antihypertensive treatment. It is also frequently employed to check the efficacy of this treatment in conditions resembling daily life. This paper will describe the effect of a number of antihypertensive drugs on ambulatory blood pressure, based on data collected by our group in the past 10 years. It will then discuss the advantages of ambulatory blood pressure in studies on efficacy of antihypertensive drugs and the importance of this approach for definition of the trough-to-peak ratio of the antihypertensive effect. Some technical and clinical problems inherent to the ambulatory blood pressure monitoring approach will also be discussed.     

Ambulatory Blood Pressure Monitoring–Derived Short‐Term Blood Pressure Variability in Primary Aldosteronism

The aim of this study was to investigate the short‐term blood pressure (BP) variability (BPV) derived from ambulatory blood pressure monitoring (ABPM) in patients with primary aldosteronism (PA), either idiopathic hyperaldosteronism (IHA) or aldosterone‐producing adenoma (APA), in comparison with patients with essential hypertension (EH) and normotensive (NT) controls. Thirty patients with PA (16 with IHA and 14 with APA), 30 patients with EH, and 30 NT controls, matched for sex, age, body mass index, and antihypertensive therapy, were studied. The standard deviation (SD) of 24‐hour, daytime, and nighttime BP; 24‐hour weighted SD of BP; and 24‐hour BP average real variability were not different between patients with PA and those with EH (P=not significant). All BPV indices were higher in patients with PA, either IHA or APA subtypes, and patients with EH, compared with NT controls (P<.001 to P<.05). ABPM‐derived short‐term BPV is increased in patients with PA, and it may represent an additional cardiovascular risk factor in this disease. The role of aldosterone excess in BPV has to be clarified.     

Visit‐to‐visit systolic blood pressure variability predicts treatment‐related adverse event of hyponatremia in SPRINT

Hypertension is a common condition and an important cardiovascular risk factor. SPRINT trial showed that the beneficial effects of targeting systolic blood pressure <120 mm Hg were accompanied by more adverse events. De‐identified SPRINT database was used for this analysis. All subjects in each group that achieved their respective target blood pressure (<120, intensive; <140, standard) were included. Only readings after reaching target blood pressure for the first time were included. Subjects that never reached target or had <2 readings upon reaching target were excluded. Coefficient of Variation (CV) of systolic blood pressure was calculated for each subject to characterize variability. Cox proportional hazards regression was used in the overall cohort as well as the intensive and standard treatment subgroups separately, to identify the effect of CV of systolic blood pressure on occurrence of hyponatremia. P<.05 was considered statistically significant. A total of 8884 subjects met the inclusion criteria; 4323 in intensive and 4561 in standard group. Two hundred and sixty five hyponatremic events occurred in the overall cohort; 168 in intensive, and 127 in standard treatment group. CV of systolic blood pressure consistently and independently predicted a greater hazard of hyponatremia on overall (HR 1.08, P<.001), as well as separate regressions by treatment arms (each HR=1.08 and P<.05). In conclusion, visit‐to‐visit systolic blood pressure variability is independently associated with a small but significant risk of hyponatremia in the SPRINT trial .     

Simultaneous Compared With Sequential Blood Pressure Measurement Results in Smaller Inter‐Arm Blood Pressure Differences

There are currently few recommendations on how to assess inter‐arm blood pressure (BP) differences. The authors compared simultaneous with sequential measurement on mean BP, inter‐arm BP differences, and within‐visit reproducibility in 240 patients stratified according to age (<50 or ≥60 years) and BP (<140/90 mm Hg or ≥140/90 mm Hg). Three simultaneous and three sequential BP measurements were taken in each patient. Starting measurement type and starting arm for sequential measurements were randomized. Mean BP and inter‐arm BP differences of the first pair and reproducibility of inter‐arm BP differences of the first and second pair were compared between both methods. Mean systolic BP was 1.3±7.5 mm Hg lower during sequential compared with simultaneous measurement (P<.01). However, the first sequential measurement was on average higher than the second, suggesting an order effect. Absolute systolic inter‐arm BP differences were smaller on simultaneous (6.2±6.7/3.3±3.5 mm Hg) compared with sequential BP measurement (7.8±7.3/4.6±5.6 mm Hg, P<.01 for both). Within‐visit reproducibility was identical (both r=0.60). Simultaneous measurement of BP at both arms reduces order effects and results in smaller inter‐arm BP differences, thereby potentially reducing unnecessary referral and diagnostic procedures.     

Hypertension,Blood Pressure Variability,and Target Organ Lesion

Hypertensive patients have a higher risk of developing health complications, particularly cardiovascular (CV) events, than individuals with normal blood pressure (BP). Severity of complications depends on the magnitude of BP elevation and other CV risk factors associated with the target organ damage. Therefore, BP control and management of organ damage may contribute to reduce this risk. BP variability (BPV) has been considered a physiological marker of autonomic nervous system control and may be implicated in increased CV risk in hypertension. This review will present some evidence relating BPV and target organ damage in hypertension in clinical and experimental settings.