Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort Study

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-