Non-genetic predictors of antihypertensive response

5.4.1 Demographic factors (Study I)

The relationships between BP response to study drugs and age, BMI, triceps skin fold thickness, WHR, weight, duration of hypertension, number of previous antihypertensive drugs, and number of affected parents were analyzed in Study I.

For bisoprolol and losartan, no significant associations of these explanatory variables with BP response were found in neither pairwise nor multivariate analysis (Table 6).

Age was positively correlated with OBP and ABP response to amlodipine and hydrochlorothiazide, even though the association with diastolic 24-hour ABP response to hydrochlorothiazide became statistically significant only after multivariate analysis.

For example, the median 24-hour systolic response to amlodipine was 4.8 mmHg higher in the highest age quartile than in the lowest quartile. Although the duration of hypertension was positively correlated with age (r=0.15, P=0.02), the associations with BP response to hydrochlorothiazide was in the opposing direction (Table 6).

BMI was negatively correlated with 24-hour systolic and diastolic ABP response to amlodipine (both r values -0.14, P<0.05), but not with OBP response.

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Table 6. Correlation matrix of blood pressure responses to study drugs with several variables.

Amlodipine Bisoprolol Hydrochlorothiazide Losartan

OBP ABP OBP ABP OBP ABP OBP ABP

Age 0.26‡/0.20† 0.24‡/0.26‡ -0.07/-0.07 0.10/0.02 0.22†/0.19† 0.19‡/0.08 0.03/-0.10 0.10/-0.10

Duration of -0.05/0.01 -0.07/-0.04 0.05/0.09 0.09/0.06 -0.09/-0.05 -0.13/-0.19‡ 0.02/0.03 -0.03/-0.01 hypertension

Number of 0.20†/0.06 0.14*/0.13 -0.08/-0.06 -0.02/0.08 0.03/-0.03 0.04/0.02 -0.01/-0.06 0.01/-0.05 antihypertensive

drugs

Number of -0.13/-0.13 0.08/0.02 -0.06/-0.03 -0.04/-0.00 -0.08/-0.02 -0.02/0.00 0.03/0.06 0.12/0.09 affected

parents

BMI -0.07/-0.01 -0.14*/-0.14* -0.01/-0.02 -0.09/-0.03 -0.03/-0.08 -0.01/0.07 -0.06/0.02 -0.10/-0.05 WHR 0.01/0.04 -0.04/-0.04 0.10/0.09 -0.02/0.02 -0.01/-0.02 -0.03/0.06 0.01/0.04 0.03/0.04

Triceps 0.01/0.04 0.03/0.02 -0.08/-0.07 -0.08/-0.12 0.09/0.01 0.17*/0.09 -0.01/-0.03 -0.07/-0.10 skinfold

thickness

BMI, body mass index; ABP, ambulatory blood pressure; OBP, office blood pressure; WHR, waist hip ratio. The values shown are Spearman’s correlation coefficients (r) for systolic / diastolic responses, and a positive coefficient indicates a better drug response with increasing value of explanatory variable.

* P < 0.05, † P < 0.01, ‡ P < 0.001.

5.4.2 Blood pressure levels (Study I)

BP levels during the placebo periods were positively associated with BP response to the study drugs (Table 7). The antihypertensive drug response to all of the study drugs was greater in the highest placebo BP quartile compared to the lowest placebo BP quartile (Study I, Figure 3). In 24-hour ABP recordings, this trend was especially pronounced for amlodipine (both systolic and diastolic pressures) and hydrochlorothiazide (systolic pressure).

There were some correlations of pulse pressure with OBP response to study drugs. Both systolic and diastolic ABP and OBP response to amlodipine, and systolic ABP and OBP response to hydrochlorothiazide were positively and statistically significantly correlated with placebo pulse pressure. In contrast, the response to bisoprolol and losartan were stable at different placebo pulse pressure levels.

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Table 7. Correlation matrix of blood pressure responses to study drugs with corresponding placebo blood pressure level.

Placebo blood pressure level

Office Ambulatory

Blood pressure response to

Amlodipine 0.39‡ / 0.35‡ 0.48‡ / 0.43‡

Bisoprolol 0.17* / 0.20† 0.21† / 0.25‡

Hydrochlorothiazide 0.21† / 0.23‡ 0.30‡ / 0.25‡

Losartan 0.14* / 0.16* 0.17* / 0.19†

The values shown are Spearman’s correlation coefficients (r) for systolic / diastolic responses.

* P<0.05, † P<0.01, ‡ P<0.001.

ABP response to amlodipine and the OBP response to hydrochlorothiazide were negatively correlated with nighttime dipping during placebo periods. The correlations were statistically significant in multivariate analysis with age and corresponding BP level on placebo included (data not shown). However, the BP response to bisoprolol and losartan were similar at different levels of nighttime BP dipping whilst on placebo.

There was a negative correlation between heart rate in OBP measurements during placebo periods to 24-hour ABP response to bisoprolol (P=0.02 for systolic and P=0.06 for diastolic response). The systolic OBP response to amlodipine was also negatively correlated with HR (P=0.03).

5.4.3 Laboratory tests (Study II)

The correlation between pretreatment laboratory tests to BP response to study drugs was analyzed in Study II. Of the laboratory tests, PRA was the most distinct predictor of the antihypertensive effect of losartan, and correlated positively with all BP responses to losartan in both pairwise and multivariate analysis (Table 8, Figure 6). In accordance with this, losartan exerted a significantly stronger antihypertensive response in the highest PRA quartile compared to the lowest quartile. Additonally, there was a positive correlation between PRA and BP response to bisoprolol (Table 8, Figure 6), with diastolic ABP being more effectively reduced in the high-renin quartile than in the low-renin quartile (Study II, Figure 1 C).

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Figure 6. Correlation of plasma renin activity with systolic ambulatory blood pressure responses to study drugs. Statistical significance was analyzed as partial correlation controlling for systolic ambulatory placebo blood pressure level and using normalized values of plasma renin activity. ABP, 24-h ambulatory blood pressure.

Baseline PRA was negatively correlated with BP response to hydrochlorothiazide, with these correlations being statistically significant in multivariate analysis with diastolic ABP and systolic OBP response (Table 8, Figure 6). The ABP response to hydrochlorothiazide was higher in the lowest, compared to the highest, PRA quartile.

There was also a weaker correlation between PRA and BP response to amlodipine (Table 8, Figure 6). The BP lowering effect of amlodipine tended to be more noticeable in the low vs. high PRA quartile, however, the correlation was only statistically significant in the pairwise analysis with systolic ABP response (Study II, Figure 1 C).

There was no significant correlation between baseline serum aldosterone levels and BP response to any of the study drugs.

Daily urinary excretion of sodium, chloride and potassium were all negatively correlated with BP response to amlodipine (Table 8). In multivariate analysis, inclusion

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of sodium excretion removed the statistical significance of chloride and potassium excretions to ABP response. The ABP response to amlodipine treatment were significantly different (P<0.05) between the lowest and highest quartiles of daily urinary excretion of sodium. No significant association was found for the response of the other three drugs with daily urinary excretion of sodium (Table 8).

Serum total calcium level was negatively correlated with BP response to amlodipine, but not to other drugs, in all measurement modes (Figure 7, Table 8). When systolic and diastolic ABP response to the study drugs was analyzed in the four quartiles of pretreatment serum calcium levels, ABP response to amlodipine was found to be significantly stronger in the lowest calcium quartile than in the highest calcium quartile (Study II, Figure 1C). In multivariate analysis, the association of serum calcium level to amlodipine response was statistically significant for all BP responses except for systolic ABP response (P=0.08).

Figure 7. Correlation of serum total calcium level with blood pressure response to amlodipine. Statistical significance was analyzed as partial correlation controlling for the corresponding placebo blood pressure level. ABP, 24-h ambulatory blood pressure; OBP, office blood pressure

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Serum total cholesterol level was negatively correlated with ABP response to amlodipine and to a lesser extent with BP response to bisoprolol, both in subjects with or without earlier statin therapy (Table 8). In addition, fasting serum glucose levels were correlated in an inverse manner with losartan response in all BP measurements.

Furthermore, there were less consistent correlations between serum triglyceride, insulin, creatinine, sodium and potassium levels to BP response to the four study drugs (Study II, Table 3).

Table 8. Correlation matrix of blood pressure responses with pretreatment laboratory test results.

Amlodipin Bisoprolol Hydrochlorothiazide Losartan

ABP OBP ABP OBP ABP OBP ABP OBP

Syst/diast Syst/diast Syst/diast Syst/diast Syst/diast Syst/diast Syst/diast Syst/diast

Renin -0.17*/-0.11 0.08/-0.02 0.15*/0.15* 0.14*/0.09 -0.16*/-0.18* -0.12/-0.16 0.20†/0.25‡ 0.22†/0.27‡

Aldosterone 0.01/-0.03 0.02/-0.04 0.05/0.08 0.03/0.03 -0.10/-0.04 -0.02/-0.07 -0.01/-0.04 0.03/0.08 dU-Sodium -0.27‡/-0.17* -0.05/-0.05 -0.05/0.04 0.05/0.09 -0.12/-0.11 -0.04/-0.06 -0.09/-0.03 0.07/0.06 dU-Chloride -0.25‡/-0.16* -0.05/-0.07 -0.03/0.05 0.09/0.14* -0.09/-0.10 -0.09/-0.07 -0.04/-0.01 0.08/0.08 dU-Potassium -0.21†/-0.14* -0.18†/-0.12 -0.07/-0.04 0.03/0.08 -0.09/-0.10 -0.09/-0.07 -0.05/-0.06 -0.01/0.05 Glucose -0.05/-0.06 0.05/0.03 0.02/0.01 -0.01/-0.07 -0.04/-0.01 -0.11/-0.10 -0.14*/-0.16*-0.17*/-0.17*

Cholesterol -0.29‡/-0.23† -0.13/-0.12 -0.13/-0.08 -0.09/-0.17* -0.02/-0.02 -0.06/-0.09 -0.04/-0.04 0.05/0.03 Calcium -0.23†/-0.27‡-0.18†/-0.16* -0.02/0.00 -0.03/0.00 -0.01/-0.07 0.03/-0.03 -0.03/0.02 -0.03/0.01

ABP, ambulatory blood pressure; OBP office blood pressure; syst, systolic; diast, diastolic; dU, daily urinary. The values shown are partial correlation coefficients (r), controlling for the corresponding placebo BP level, for serum values unless otherwise indicated. A positive r value indicates a better antihypertensive response with increasing explanatory variable value. * P< .05, † P< .01, ‡ P< .001 for pairwise analysis.