Comparison of a Chronotherapeutically Administered β Blocker vs. a Traditionally Administered β Blocker in Patients With Hypertension

Abstract

Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of β blockers during this period may decrease cardiac workload, particularly in β‐blocker sensitive patients. The impact of a new chronotherapeutic β blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed‐release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty‐four‐hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24‐hour blood pressure (−9.01‐6.9 mm Hg and −10.41‐7.7 mm Hg, respectively). The top 25% of responders to highdose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were −8.0/‐6.7 mm Hg and −7.61‐5.8 mm Hg, respectively. Mean blood pressure reductions in the β‐blocker sensitive patients (n=11) between 6 a.m. and noon were −15.2/‐11.9 mm Hg on INP and ‐8.0/‐4.6 mm Hg on ILA. Heart rate reduction was −14.1 bpm and double product reduction was −3319 in the INP patients between 6 a.m. and 12 noon compared with −10.5 and −2209 in the ILA patients. This study suggests that INP and ILA are effective once‐a‐day β blockers, but the use of delayed‐release propanolol results in a greater reduction in double product between 6 a.m. and noon in β‐blocker sensitive patients than does traditionally dosed propranolol.

It has been demonstrated that the peak incidence of cardiovascular (CV) events occurs between 6 a.m. and 12 noon, and coincides with the rapid early morning surge of blood pressure (BP). ¹ , ² , ³ There are now several cross‐sectional and outcome studies which suggest a cause‐and‐effect relationship between rapid changes in BP and CV disease. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Although none of the outcome studies to date have demonstrated that a decrease in the morning BP surge will result in fewer CV events, a greater emphasis has been placed on the importance of early morning BP control. Since it is frequently logistically difficult to obtain peak efficacy during this early morning period, because drugs taken in the morning may be less effective during this period, and drugs taken at night may peak too early, there has been a focus on the development of chronotherapeutic agents designed to provide peak plasma levels of medication during the period of arousal from sleep.

Apart from the rapid increase in BP that occurs in the morning, which may impact the onset of cardiac events, there are also increases in heart rate (HR), which follows a similar circadian pattern to that of BP. ⁴ This results in significant increases in myocardial workload during this period, which may also be important in the pathogenesis of CV disease. ⁴ For these reasons, β blockade during this early morning period may be desirable because of the impact on BP, HR, and cardiac workload.

Delayed‐release propranolol (Innopran XL; Reliant Pharmaceuticals, Inc., Liberty Corner, NJ) is a recently developed chronotherapeutic agent designed to be taken at bedtime. Through a delayed‐release delivery system, it provides peak plasma levels during the early morning period. Since it has been demonstrated that β blockers have a flat dose‐response curve, ⁹ it is not known whether a chronotherapeutic agent will have any additional impact on BP, HR, or cardiac workload in response to high plasma levels in patients at steady states. Clinical experience has shown that among hypertensive patients there is a group that is more responsive to β blockers (“β‐blocker sensitive”) and demonstrates a dose‐response curve with increasing plasma levels of β blockers.

In this study, a crossover design was used to compare a chronotherapeutic delayed‐release propranolol dosed as 120 mg at bedtime (Innopran XL) compared with propranolol 120 mg dosed in the morning (Inderal LA; Wyeth Pharmaceuticals Inc., Philadelphia, PA) to compare pharmacokinetics and hemodynamics of these agents with a focus on morning BP and cardiac workload. We also attempted to isolate patients who are β‐blocker sensitive and compare the effects of these agents in these individuals.

Patients

Patients between 18 and 75 years of age were recruited for this study. To be eligible, patients were required to have stage 1 or stage 2 hypertension, defined as a mean seated diastolic BP (DBP) of 95‐114 mm Hg and a mean daytime ambulatory DBP (8 a.m. to 4 p.m.) of 90‐114 mm Hg, following a 4‐week single‐blind placebo run‐in period. Patients with a mean DBP ≥115 mm Hg and/or a mean systolic BP (SBP) ≥200 mm Hg at any time during the study were excluded. The study protocol was approved by a local ethics committee and all patients signed an approved informed consent form before entry into the study. The study was conduction in accordance with all the principals of the Declaration of Helsinki.

Study Design

This was a multicenter, double‐blind, double‐dummy, randomized, blinded end point, crossover study. After completing written informed consent and an initial screening visit, all antihypertensive medications were discontinued and patients entered a 4‐week singleblind placebo run‐in period. Patients who qualified based on office BP measurements were subjected to 24‐hour ambulatory BP monitoring (ABPM). Patients who met both office and ABPM criteria were randomized to traditional propranolol (Inderal LA) 80 mg dosed at 8 a.m. or to delayed‐release propranolol (Innopran XL) 80 mg dosed at 10 p.m. Following 1 week of this initial treatment, patients receiving Inderal LA 80 mg were force‐titrated to Inderal LA 120 mg dosed at 8 a.m. for a period of 4 weeks. Patients on Innopran XL 80 mg were force‐titrated to Innopran XL 120 mg dosed at 10 p.m. for a period of 4 weeks.

At the end of the first 4 weeks of double‐blind treatment, patients had an ABPM applied in the normal work/home environment for a 24‐hour period, during which they continued their doubleblind treatment. Within 48 hours of removal of the ABPM, patients were admitted to the pharmacokinetic (PK) unit for 36 hours of PK analysis and BP measurements. During this period they were dosed in the usual way with this double‐blind medication. All patients remained in the PK unit for the 36‐hour measurement period, during which all procedures and meals were standardized for the patients.

At the end of the initial 36‐hour PK period, patients were crossed over to the opposite treatment. Patients on Inderal LA 120 mg were dispensed Innopran XL 120 mg, and patients on Innopran XL 120 mg were dispensed Inderal LA 120 mg, for a period of 4 weeks. Following this 4‐week period, all patients repeated the ABPM in the normal work/home environment for a 24‐hour period, during which they took their medication in the usual manner. Within 48 hours of removal of the ABPM, patients were readmitted to the PK unit for a second 36 hours of PK analysis and BP measurements.

Patients were then titrated off their study medication by decreasing the respective doses of each of the medications to 80 mg for 3 days, following which all patients exited the study.

BP Measurements

Twenty‐four hour ABPM was performed using the Spacelabs 90207 device (Spacelabs Inc., Issaquah, WA). BP was measured at 20‐minute intervals throughout the dosing period. The same Spacelabs devices were used to measure BP during the 35‐hour PK visit, during which BP was measured at hourly intervals and with each PK draw. Office BP was measured using a standard sphygmomanometer. Office readings consisted of the mean of three measurements taken 2 minutes apart.

PK Measurements

All patients were admitted to a standardized PK unit for a 36‐hour period. The PK period was divided into Day 1, which was from 10 p.m. to 10 p.m. (the following evening) and Day 2, which was from 10 p.m. to 9 a.m. the following morning. Patients were dosed in the usual way with their double‐blind medication during this period. Samples for plasma drug concentration measurements were drawn at the following times: Day 1: 10 p.m. (immediately before dosing), immediately after dosing, and at hours 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 post‐dose. Day 2: at hours 26, 28, 30, 32, and 34 post‐dose. ABPM was initiated at 10 p.m. on Day 1 and measured BPs hourly throughout the PK period. The BP monitor was manually operated to coincide with the PK blood samples. Blood samples were taken after the BP measurement corresponding to the draw had been completed.

Statistical Analysis

The safety‐evaluable population included all patients who had taken at least one dose of double‐blind study drug. The intent‐to‐treat population included all safety‐evaluable patients who had both a valid baseline and valid postbaseline primary or secondary efficacy data. All statistical analyses were performed using a statistical significance level of 0.05 unless otherwise specified. All p values generated were two‐sided. Background and demographic characteristics are presented by treatment group. Continuous variables are summarized by descriptive statistics. Treatment groups were compared using analysis of variance. If data were not normally distributed, an equivalent nonparametric method such as the Wilcoxon rank sum test was used. Discrete variables were summarized by frequencies and percentages; treatment groups were compared using the chi‐square test.

RESULTS

A total of 63 patients were screened for this study and 44 patients were randomized to active treatment. The 19 patients who were not randomized were either screen failures or run‐in failures, with the majority being excluded for not fulfilling BP criteria or for noncompliance. Three patients were excluded following randomization. Of the three excluded patients, one was excluded by the investigator for being uncooperative and noncompliant with study medication, one for being off study medication for a significant period of time, and one patient was removed for alcohol abuse. Thus, the safety population included 44 patients and the intent‐to‐treat population included 41 patients.

The baseline demographics and patient characteristics for the safety population are summarized in Table I. Patient demographics and characteristics are divided by treatment sequence and are also shown for the entire study population. There were no significant differences between the treatment sequence groups for any of the baseline demographics or clinical characteristics.

Table I.

Baseline Demographics

Parameter	Innopran XL to InderalLA	Inderal LA to InnopranXL	Total
Number	23	21	44
Age (yr) (mean ± SD)	54.1±8.61	52.6±8.44	53.4±8.46
Male (n)	18	13	31
Female (n)	5	8	13
Caucasian (n)	14	13	27
African American (n)	4	1	5
Asian (n)	0	3	3
Hispanic (n)	3	2	5
Other (n)	2	2	4
Office BP (mm Hg) (mean ± SD)
Systolic BP	151.7±14.99	151.4±13.01	151.6±13.9
Diastolic BP	100.4±4.16	99.5±4.78	100.0±4.44
Mean daytime ambulatory BP monitoring (mm Hg) (mean ± SD)
Systolic BP	157.8±15.18	158.6±10.57	158.2±13.0
Diastolic BP	99.0±6.51	100.6±6.09	99.8±6.30
BP=blood pressure

Treatment with Innopran XL resulted in significant decreases in mean 24‐hour SBP (−9.0±12.2 mm Hg; p<0.0001) and DBP (−6.6±8.4 mm Hg; p<0.0001) from baseline levels. Similarly, treatment with Inderal LA resulted in significant decreases in mean SBP (−10.4±11.7 mm Hg; p<0.0001) and mean DBP (−7.7±7.7 mm Hg; p<0.0001) from baseline levels. There were no significant differences between the treatments for either SBP or DBP. It should be noted that these BPs were derived from the ABPM conducted in the home/work environment.

The area under the plasma concentration time curve (AUC) was analyzed on the log‐transformed scale where AUC_0–24 represents a dosing interval of 24 hours. AUC_0–24 was calculated using the linear trapezoidal rule for the period from dose administration up to 24 hours postdose. The AUC_0–24 for Innopran XL was calculated for the period 10 p.m. to 10 p.m. and the AUC_0–24 for Inderal LA was calculated for the period 8 a.m. to 8 a.m. The AUC_0–24 for Innopran XL was 3140.5±1885.9 ng • h/mL and for Inderal LS it was 3366.6±2183.9 ng • h/mL. Thus, there were no statistically significant differences in sequence effect, period effect, or treatment effect between the groups.

Trough BP reductions and pharmacokinetics were calculated and compared for the two groups. Due to the difference in timing of dose, the trough period for Innopran XL was defined as 6 p.m. to 10 p.m. and the trough period for Inderal LA was 4 a.m. to 8 a.m. (Figure). The reduction in mean trough SBP for patients treated on Innopran XL was −8.0±14.8 mm Hg (p<0.002 vs. baseline) and the reduction in mean trough DBP was −6.7±10.0 mm Hg (p<0.0001 vs. baseline). The mean reduction in trough SBP in patients treated with Inderal LA was −7.6±15.0 mm Hg (p<0.003 vs. baseline) and the mean reduction in trough DBP was −5.8±11.5 mm Hg (p<0.004 vs. baseline). Again, there were no significant differences between the groups in trough BP.

The trough AUC in patients treated with Innopran XL was 505.9±307.5 ng • h/mL, which was significantly greater (p<0.02) than the trough AUC in patients treated with Inderal LA (398.7±266.3 ng • h/mL).

The AUC and BP reductions were also compared for the period 6 a.m. to 12 noon. AUC between 6 a.m. and 12 noon was 911.1±546.4 ng • h/mL for patients treated with the delayed release Innopran XL. This is significantly (p<0.02) greater than those treated with traditionally dosed Inderal LA (689.2±435.7 ng • h/mL). However, despite these differences in PK levels during this time period, there were no significant differences in mean SBP or DBP reductions during this time when comparing the groups. The mean reduction in BP between 6 a.m. and 12 noon in the Innopran XL treated patients was −9.4±12.3/‐6.7±8.4 mm Hg (p<0.0001 vs. baseline) and in the Inderal LA treated patients was −10.9±12.1/−7.1±7.6 mm Hg (p<0.001 vs. baseline). The mean reduction in HR for each group during this time period was −10.29±5.84 bpm and −10.83±7.62 bpm respectively.

To isolate the β‐blocker sensitive patients, the 25% of patients with the greatest DBP reductions during the period 6 a.m. to 12 noon on Innopran XL were compared with the same patients treated on Inderal LA to determine if the differences in plasma levels of drug during this period had an impact on BP. The reduction in mean SBP in this group of patients (n=11) during the period 6 a.m. to 12 noon was −15.2±12.7 mm Hg when treated on Innopran XL. The same 11 patients treated on Inderal LA had mean SBP reductions of −8.0±16.6 mm Hg during the period 6 a.m. to 12 noon. The mean reduction in DBP on Innopran XL was −11.3±9.1 mm Hg, which was significantly greater (p<0.04) than when treated on Inderal LA (−4.6±8.5 mm Hg). Reductions in HR during this period were −14.1±4.63 bpm when treated on Innopran XL and −10.3±5.9 bpm while treated on Inderal LA. Double product was calculated for the patients during this period of 6 a.m. to 12 noon under both treatment conditions. With Innopran XL, the reduction in mean double product for these patients was −3318.5±1365.2. On Inderal LA, it was −2209.1±1582.8. Peak levels of Innopran XL occurred during the period 6 a.m. to 9 a.m. BP, HR and double product were calculated during this 3‐hour period to assess whether greater responses occurred with high plasma levels of Innopran XL. Table II demonstrates reductions for each of these parameters for the 11 β‐blocker sensitive patients with each of the drugs.

Table II.

Changes in Mean Blood Pressure (BP), Heart Rate (HR), and Double Product Between 6 a.m. and 9 a.m. in β‐Blocker Sensitive Patients (n=11)

	Innopran XL	Inderal LA
Systolic BP (mm Hg)	−15.0±12.9	−6.9±13.2
Diastolic BP (mm Hg)	−12.9±10.6	−3.5±9.9
HR (bpm)	−13.8±6.1	−10.4±6.1
Double product (systolic BP × HR)	−3189.5±1360.6	−2139.8±1470.8
All values are mean ± SD

DISCUSSION

In this study we have shown, using a double‐blind crossover study design, that patients treated with the new chronotherapeutic propranolol, Innopran XL, or with Inderal LA, both experienced similar highly significant reductions in mean 24‐hour BP. In addition, both agents provided 24‐hour BP control with once‐a‐day dosing. Plasma levels with the chronotherapeutic agent Innopran XL, which is designed to provide peak plasma levels of the drug during the early morning period, were, as expected, significantly higher than Inderal LA during this period. Despite this difference in plasma levels of drug, however, there were no differences in BP between patients treated with these agents during this time period.

This finding is not entirely surprising, as it has been previously well demonstrated that β blockers have a flat dose‐response curve. In a recently published study ⁹ in which patients were given increasing doses of Innopran XL (80 mg, 120 mg, 160 mg, and 640 mg) dosed at night, the maximal reduction in mean 24‐hour BP was achieved at 120 mg, and further increases in dose were not associated with greater BP reductions. Similar findings have demonstrated that mean BP reduction between 6 a.m. and 12 noon and mean BP reduction at trough are similar. ⁹ These findings would suggest that once a steady state is achieved at propranolol doses of 120 mg, further increases in plasma levels of propranolol have no impact on BP.

There have been reports, however, of groups of patients who are β‐blocker sensitive, who tend to have a hemodynamic dose‐response curve to increased β‐blocker levels. In this study, the plasma levels of propranolol were higher in patients treated with the chronotherapeutic formulation of propranolol. This provided an opportunity to assess whether there were β‐blocker sensitive patients in our patient population. The top 25% of patients with the greatest reduction in SBP and DBP between 6 a.m. and 12 noon when treated with Innopran XL were compared with the same patients treated on Inderal LA. The fact that these same patients had smaller reductions on Inderal LA than the group mean (−8.0/−4.6 mm Hg compared with −11.3/−7.5 mm Hg) would suggest that they would require higher β‐blocker levels than the general population to elicit a typical hemodynamic response—a greater BP reduction in response to increasing doses of drug.

Table III compares the baseline characteristics of the patients who were β‐blocker sensitive to the remaining patients. There were no significant differences between the groups. Although it is believed that reducing BP during the early morning period may decrease CV disease, it should be emphasized that this has not yet been proven in well conducted outcome studies.

It has been reported that the double product (SBP×HR) is a sensitive marker of cardiac workload or myocardial oxygen demand. ⁴ Since HR has a similar circadian pattern to that of BP, the double product when plotted out over a 24‐hour period has a similar pattern to that of BP, with a rapid early morning surge. During this early morning period the incidence of myocardial ischemia is increased. A reduction in myocardial oxygen demand during this period may be beneficial, although studies have not yet proved that this results in better CV outcome. By decreasing BP and HR, β blockers have a significant impact on double product and oxygen demand. Previous studies have shown that in post‐myocardial infarction patients, β blockers are cardioprotective—there is a significant correlation between the degree of HR reduction and CV events. ⁸

Since we could not differentiate β‐blocker dose responders from those who are not dose responders, chronotherapeutic β blockers may provide an important treatment option. While those who are not dose responders will have similar BP reductions with a traditional β blocker, β‐blocker sensitive responders, who may represent approximately 25% of the hypertensive population, will have a greater hemodynamic response to a chronotherapeutic β blocker.

One limitation of this study is that only 41 patients were included in the intent‐to‐treat group.

However, the study was performed as a crossover design, which increases its power. Nonetheless, future studies would be important to further evaluate the findings of this study.

Disclosure: This study was supported by a grant from Reliant Pharmaceuticals, Inc., Liberty Corner, NJ.