Blood Pressure Control in Hypertensive Patients With Left Ventricular Hypertrophy. The VIIDA Study

INTRODUCTION

Hypertension (HT) is a vitally important risk factor for the development of cardiovascular disease and a significant public health problem. It has been reported that for every 20-mm Hg increase in systolic pressure and every 10-mm Hg increase in diastolic pressure, the risk of cardiovascular events doubles in individuals with blood pressure values between 115/75 and 185/115 mm Hg.¹ For this reason, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) has classified blood pressure into different categories, each of which is related to a different estimation of morbidity and mortality.²

Various clinical trials have shown that blood pressure (BP) control with the use of pharmacological treatment can reduce adverse events related to this factor.³ Despite this evidence, BP control remains insufficient. In Spain, according to the CARDIOTENS study,⁴ only 36% of hypertensive patients with associated heart disease presented BP values <140/90 mm Hg, and the percentage is much lower in the subgroup of patients with diabetes.⁵

One of the earliest cardiovascular alterations produced by HT is left ventricular hypertrophy (LVH), which, when detected on electrocardiography (ECG), provides valuable prognostic information (predicting cardiovascular and cerebrovascular disease)^6,7 and aids in the decision of which drug regimen is most suitable.⁸ Both electrocardiography and echocardiography allow assessment of LVH regression, which implies an improvement in the prognosis.⁹

The aim of this study is to determine the degree of BP control in hypertensive patients with left ventricular hypertrophy as defined by the ECG and investigate variables associated with poor control, with a particular focus on the diabetic patients included in the study.

METHODS

The VIIDA study in a multicenter, cross-sectional study performed in outpatient cardiology units all over Spain, following approval by an independent ethics committee for clinical investigation. The study was designed in 2003 by the Hypertension Section of the Spanish Society of Cardiology (Sección de Hipertensión de la Sociedad Española de Cardiología) in conjunction with the Outpatient Cardiology Section of the Spanish Society of Cardiology (Sección de Cardiología Extrahospitalaria de la Sociedad Española de Cardiología), and 200 cardiologists from these 2 sections participated. Data collection took place between April 2003 and November 2004. Consecutive patients diagnosed with HT were included, with no limits as to age or a history of cardiovascular disease in outpatient cardiology units. Patients were invited to participate by the investigating physicians, and after receiving information on the study and signing a consent form, the study variables were collected from their medical records. When it was deemed necessary, additional examinations were performed.

The data were compiled in a questionnaire. In the first phase, consecutive hypertensive patients who came to the unit were screened. The initial questionnaire collected data on HT history, age, sex, weight, height, cardiovascular risk factors, and cardiovascular disease. All patients underwent ECG study to investigate LVH, which was defined according to the criteria of Sokolow-Lyon (sum of the R-wave in lead V₅ or V₆ and the S-wave in lead V₁ >35 mm) or the Cornell voltage criteria (sum of the R-wave in lead aVL and the S-wave in lead V₃ >20 mm in women or >28 mm in men), or both assessment systems.

In the second phase, only patients with LVH on ECG study were analyzed. Demographic data were obtained (age and sex), anthropometric data (weight [kg] and height [cm]), cardiovascular risk factors (smoking, diabetes, hypercholesterolemia), and the course or history of cardiovascular disease (myocardial infarction, angina, intermittent claudication, heart failure, and stroke). Biochemical data were analyzed (plasma concentrations of total cholesterol, low-density lipoproteins [LDL-C] and high-density lipoproteins [HDL-C], triglycerides, baseline blood glucose, uric acid, and serum creatinine). In addition, glomerular filtration was determined from the MDRD-4 formula, which includes the variables creatinine, age, sex, and race. All data were obtained prospectively, except the analytical values, for which values obtained up to 6 months before data collection were used.

Blood pressure was measured with a mercury sphygmomanometer according to standard methods. The patient was asked to rest for 5 minutes, and after that time, 3 BP measurements were taken at 2-minute intervals. The mean of the last 2 determinations was considered the patient's BP. Based on the guidelines of the European Society of Hypertension and the JNC-7, BP was considered controlled at <140/90 mm Hg, and in diabetics at <130 mm Hg systolic and <80 mm Hg diastolic pressure.

Statistical Analysis

Qualitative variables are presented with their frequency distribution. Quantitative variables are expressed as the mean and standard deviation (SD). Associations between qualitative variables were assessed with the χ² test or Fisher exact test. The Student t test for independent samples was used to analyze the behavior of the quantitative variables for each of the independent variables. In all cases, the distribution of the variable was confirmed against the theoretical models, testing the hypothesis of homogeneity of variances. In these tests, the null hypothesis was rejected with a type 1 error or an alpha error of <.05.

Binary logistic regression models (multivariate analysis) were built to explain the independent association between variables showing a relationship with the dependent variable (BP control) in the bivariate analysis at a significance level of P<.01. Variables were introduced in the model using the forward conditional method. The statistical analysis was performed with SPSS version 11.0 (Chicago, Illinois, USA).

RESULTS

Baseline Characteristics

Over the study period, 16 123 consecutive patients with HT were screened, and 4037 (25.04% of the population) presented LVH as defined by the above-described criteria. Among the patients with LVH, 3962 (98.1%) were assessable, including 47.6% women and 52.4% men, with a mean age of 68.16 years and mean BMI of 27.8. Among the total cohort, 27.3% of patients (1083) were diabetic (91.6% type 2), 56.8% had dyslipidemia, and 13.8% were smokers. The mean number of drugs used was 2.26: 55.4% of patients were receiving diuretics, 47.8% beta-blockers, 37.5% calcium channel blockers, 43.7% angiotensin-converting enzyme (ACE) inhibitors, 39.9% angiotensin receptor blockers (ARB), and 0.4% alpha-blockers.

The patients' cardiovascular diseases at the time of recruitment for the study are summarized in Table 1.

Differential Characteristics Between Diabetic and Nondiabetic Patients

Diabetic patients were older and more likely to have a history of cardiovascular diseases (infarction, angina, stroke, peripheral vascular disease, and heart failure). There were no differences with regard to LVH characteristics on ECG. The mean number of drugs used was considerably higher in the subgroup of patients with diabetes, as well as the percentage of ACE inhibitor use as treatment; use of the remaining drugs was similar to that of nondiabetic patients (Table 2).

Blood Pressure Values and Degree of Control

Only 8.1% of patients with diabetes were well controlled; that is, systolic and diastolic BP were <130 mm Hg and <80 mm Hg, respectively. Among the nondiabetic population, 22.4% were controlled (<140/90 mm Hg). Differences in the degree of control between the 2 subgroups were significant (P<.001). As to systolic pressure alone, 23.6% of nondiabetic patients had controlled systolic BP, whereas only 10.8% of diabetic patients were controlled (systolic BP <130 mm Hg). The degree of diastolic BP control was also greater in the nondiabetic population (52.1% with diastolic BP <90 mm Hg) versus diabetic patients (26.2% with diastolic BP <80 mm Hg).

After stratification of the population according to BP values (1 stratum per each 10 mm Hg), we observed that somewhat more than 90% of the nondiabetic population presented a diastolic BP less than one stratum above normal (ie, up to 100 mm Hg) whereas in diabetic patients the proportion was around 75% (diastolic BP up to 90 mm Hg) (Table 3). In addition, around 52% of nondiabetic patients had systolic BP up to 150 mm Hg, whereas approximately 35% of patients with diabetes had systolic BP up to 140 mm Hg (Table 4).

Epidemiological Differences Between Controlled and Noncontrolled Patients

As compared to well controlled patients, the poorly controlled group included more women (42% vs 48.9%; P=.001), obese patients, (21.6% vs 25%; P=.045), and patients with diabetes mellitus (11.3% vs 28.9%; P<.0001). There were no differences between the subgroups with regard to age or percentage of smokers.

As to the analysis of differences in associated diseases, well controlled patients presented a higher prevalence of cardiovascular disease (64.1% vs 55.6%; P<.001), mainly atrial fibrillation (27.3% vs 23.6%; P=.04) and myocardial infarction (29.2% vs 24.6%; P=.03), and a lower prevalence of peripheral vascular disease (10.2% vs 13.5%; P=.04); there were no differences with respect to the history of angina, stroke, heart failure, creatinine values, or glomerular filtration, as estimated by the MDRD-4 formula. On electrocardiography, poorly controlled patients presented higher-voltage waves in the leads consistent with the criteria for LVH (Table 5).

With regard to treatment, both well controlled and poorly controlled patients were taking a similar number of drugs on average. There were no differences between the groups in the use of diuretics, beta-blockers, calcium channel-blockers, ARBs, or alpha-blockers, but ACE inhibitor use was higher in controlled patients (Table 5) and in the diabetic group (Table 2).

Predictors of Poor Blood Pressure Control

In the multivariate analysis, which included clinical variables of known value for BP control (age, sex, personal history of cardiovascular disease, diabetes, renal function, body mass index, electrocardiographic parameters, and treatment administered), the only independent predictors of poor control were diabetes (odds ratio [OR]=3.2; 95% confidence interval [CI], 2.7-4.7), female gender (OR=1.18; 1.02-1.33), and increased voltage in lead V₅ of the ECG, which refers to greater LVH (OR=1.027; 1.01-1.03 per millimeter), as well as body mass index (OR=1.03; 1.00-1.05), whereas a history of established cardiovascular disease was a protective factor against poor BP control (OR=0.57; 0.48-0.70) (Figure 1).

Figure 1. Predictors of poor blood pressure control. Multivariate analysis (logistic regression) adjusted for age, sex, diabetes, use of angiotensin-converting enzyme inhibitors, body mass index, voltages in V₁, V₅, and aVL, and cardiovascular disease. BMI indicates body mass index; CVD, cardiovascular disease; DM, diabetes mellitus; V₅, voltage in lead V₅ (mm).

DISCUSSION

According to the findings of the VIIDA study, hypertensive patients seen in outpatient cardiology units present a high prevalence of ECG-proven LVH together with an elevated number of cardiovascular risk factors. Other studies have reported a lower prevalence of LVH in patients with hypertension,^10,11 but the populations differed, since the patients had been recently diagnosed and were at a lower risk. Published studies in our setting show percentages similar to those reported herein, with LVH observed in 20% of patients seen in primary care centers¹² and 25.4% of patients seen in hospital units.¹³ The diagnosis of LVH is important because it allows stratification of the patient's prognosis and establishment of adequate treatment, which improves the patient's risk profile and regression of the disease. There are several methods for determining LVH, but the most useful and widely available is ECG study, which, by measurement of the voltage values in several leads, provides a great deal of information that facilitates both the diagnosis and follow-up.¹⁴

The subgroup of hypertensive diabetic patients with LVH is particularly important because they have a poorer prognosis and their management is more complex. In the present study, this subgroup was older, the majority were women, and they had a more unfavorable cardiovascular profile (higher prevalence of cardiovascular disease, angina, stroke, etc) than patients without diabetes, and these circumstances were associated with poorer BP control, despite the fact that both subgroups received similar pharmacological treatment. These findings are in keeping with those obtained in a substudy of the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study,¹⁵ performed in 1195 patients with LVH and diabetes who presented a higher body mass index, greater cardiovascular risk according to the Framingham tables, and a higher prevalence of cardiovascular disease, with a lower percentage of smokers. In the LIFE study, patients were randomized to treatment with losartan or atenolol, and the BP values obtained were similar in the 2 treatment groups; the therapeutic end point (systolic BP <140 mm Hg) was attained in only 40% of patients. In our sample, the results for BP control were poorer, since it is not an interventional study and the values according to current guidelines² are lower than those used in the LIFE substudy.

Blood pressure control in the present study was suboptimal, particularly in patients with diabetes, in whom it did not reach 9%, although the proportion of nondiabetic patients was somewhat better at 22.5%. Although these results are worrisome, they are similar to the reported findings from other recent studies in our setting. For example, in the ERIC-HTA study (an epidemiological study to assess the risk of stroke in the hypertensive Spanish population spontaneously consulting at health centers), HT was well controlled in only 25.1% of nondiabetic and 5.6% of diabetic patients.¹⁶

Nonetheless, a series of factors have shown that BP measurement in the outpatient setting tends to exaggerate and give a more pessimistic vision of reality. It is known that recording BP in a patient who is seated rather that lying down results in a mean increase of 5 mm Hg above the true values. In addition, if the patient's back is not supported by the back of the chair, the increase is 6 mm Hg, and if the patient's legs are crossed, the BP increase is 6-8 mm Hg. This tendency can also be explained by the fact that values are rounded up in nondigital measuring devices, by treatment-related factors (non-compliance or low doses), and by the environment in which BP is measured.

In the current study, patients were stratified by BP values to determine the percentage that come close to attaining the therapeutic objective while not actually reaching it, which might somehow reduce the magnitude of the problem. On stratification of the study population into subgroups of 10 mm Hg (Table 4) and considering BP control acceptable in patients with systolic BP and diastolic BP one stratum above normal, that is, ¾150/100 mm Hg for nondiabetic and ¾140/90 mm Hg for diabetic patients (attributable to possible error in BP measurement in the outpatient setting), we found that the percentage of well controlled patients increased considerably. This might justify the underprescription of medication in these patients, with the physician recognizing that BP measurement in the office tends to yield results somewhat higher than the true values. Nevertheless, it should remain very clear that the values taken as objectives should be those recommended in clinical practice guidelines, which have proven to reduce cardiovascular complications.

As to the determinants of good BP control, a history of cardiovascular disease (ischemic heart disease, atrial fibrillation) was particularly important in this regard,^17,18 whereas factors such as obesity, diabetes, and female gender predisposed to poor BP control. In general, the main reasons for this are the following: first, patients with a history of cardiovascular disease are better managed (in the present study, mean number of antihypertensive drugs was higher, 2.65 [1.34] vs 2.4 [1.25]; P<.001) and more closely monitored, probably because of greater involvement on the part of physicians, the patients themselves, and those around them; second, the degree of control in patients with diabetes is stricter and therefore harder to adhere to; and third, it has been demonstrated that treatment in women and obese persons is suboptimal. However, other recognized factors predictive of poor BP control reported in various studies (elevated creatinine levels, history of stroke, and number of antihypertensive drugs used) ¹⁹ were not identified as such in the present study. Another important finding obtained in this study is the relationship between the degree of LVH and BP control: patients with higher-voltage recordings in V₅ presented poorer BP control.

Contrary to what might be expected, poorly controlled patients took the same number or more drugs than those who were well controlled, with no significant differences regarding the classes of drugs taken. One possible explanation for this might be that the degree of control would depend, among other factors, on the stage of vascular disease: in advanced phases, BP control would be very difficult²⁰ because of the established injury to the vessel wall, particularly in populations who are less sensitive to their status and have shown poorer compliance (women and obese patients). Another possible reason is that in cases where adherence to therapy is poor, the cardiologist might add drugs to the patient's regimen without first making sure that the patient is complying with the former prescription.

The limitations of this study include those inherent to any observational study that does not allow randomization and limits prevalence calculations, the absence of data from hypertensive patients without LVH to perform comparisons, and the errors derived from BP measurement (due to the use of non-uniform devices, with differences in cuff size and calibration, etc), although measurements were performed according to current recommendations as is done in other studies on HT. It should be kept in mind that the results cannot be applied to the general population, but only to those attended in the cardiology outpatient setting. The large sample of patients with a high prevalence of ECG-proven LVH and associated comorbid conditions seen in outpatient units in our area makes the results obtained worthy of note in our setting.

In conclusion, patients with HT consulting in cardiology outpatient units present a high prevalence of LVH detected by ECG study and considerable comorbidity associated with poor BP control despite combined treatment. This is particularly true for diabetic patients, whose BP control according to current guidelines is minimal.

ABBREVIATIONS
ACE: angiotensin-converting enzyme
ARBs: angiotensin receptor blockers
BMI: body mass index
BP: blood pressure
LVH: left ventricular hypertrophy
OR: odds ratio

The first and second authors made similar contributions in conducting the study and publishing the results.

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Correspondence: Dr. L. Fácila Rubio.
Servicio de Cardiología. Hospital Provincial de Castellón.
Avda. Dr. Clara, 19. 12002 Castellón de la Plana. España.
E-mail: [e-mail]

Received March 14, 2007.
Accepted for publication September 10, 2007.