An Effectiveness Study Comparing Algorithm‐Based Antihypertensive Therapy With Previous Treatments Using Conventional and Ambulatory Blood Pressure Measurements

Abstract

Effectiveness trials in hypertension enable the efficacy and safety of new drugs to be compared with previous therapy. Since these open‐label trials could inadvertently be influenced by observer bias, this study has used ambulatory blood pressure monitoring (ABPM) to provide a rigorous blinded end point to validate the study conclusions. The study was performed in 675 patients with stage 1 or 2 hypertension despite receiving single‐agent or fixed‐dose combination therapy. After baseline ABPM, the previous treatment was replaced by telmisartan 40 mg daily; if control (office blood pressure <140/90 mm Hg) was not achieved in 2 weeks, the dose was increased to 80 mg, and if necessary, a fixed combination with hydrochlorothiazide 12.5 mg was used after a further 4 weeks. ABPM was repeated after 4 weeks on final therapy. Overall, 50% of patients finished on monotherapy and 50% on combination therapy. By office measurements, there was a decrease (mean ± SEM) of 16.8±0.5/10.3±0.3 mm Hg (p<0.001) when telmisartan‐based treatment replaced previous treatment; by ABPM, the decrease was 8.2±0.4/5.0±0.2 mm Hg (p<0.001). The decreases were significant for comparisons with each of the prior drug classes. A treatment algorithm based on the angiotensin receptor blocker, telmisartan, was confirmed by the blinded end point of ABPM as an efficacious alternative to other antihypertensive regimens in clinical practice.

Formal clinical trials that measure safety and efficacy are part of the registration process for new drugs. Although such studies provide useful information about drug effects, they do not necessarily provide information about the value of such agents in clinical practice. For this reason, effectiveness studies that are typically performed by practicing clinicians in the community are designed to evaluate the practicality and usefulness—from both a practitioner and patient point of view—of newly approved drugs and to compare them with other products. The treatment of hypertension strongly lends itself to this process. Moreover, since it is now well known that this condition is not optimally treated in the community setting, ¹ and that the blood pressure (BP) goals recommended by guidelines committees ² , ³ are rarely achieved, effectiveness studies provide an opportunity to explore approaches that might improve management of this common condition.

The angiotensin receptor blockers (ARBs) are the newest class of antihypertensive agents available. They are efficacious and well tolerated, although there may be differences among members of this class in achieving recommended BP goals. ⁴ , ⁵ Telmisartan is a long‐acting ARB that, in formal clinical trials, has been shown to sustain its efficacy through the early morning hours near the end of the dosing interval. ⁵

This report describes an effectiveness trial in which the efficacy of telmisartan, as single therapy or in fixed combination with hydrochlorothiazide (HCTZ), was compared with previously administered antihypertensive agents. This report describes data obtained from a cohort of previously‐treated hypertensive patients who were included in a longer therapeutic trial. ⁶ The study was carried out mainly by office‐based primary care physicians. Because the accuracy of findings in open‐label trials of this type could potentially be affected by observer bias, the principal BP measurements, at baseline and at the end of treatment with telmisartan‐based therapy, were performed by ambulatory BP monitoring (ABPM). Because the data produced by this technique are submitted directly to a data center remote from the trial sites, the key study end points are fully blinded, preserving the integrity of the trial. A further property of ABPM is that it is reproducible over time and eliminates so‐called placebo effects, thereby enabling valid comparisons of efficacy between previous and subsequent treatment regimens. ⁷ , ⁸

Study Design

This trial was conducted as a prospective, open‐label, blinded end point, phase IV practice‐based trial designed to evaluate the antihypertensive efficacy of telmisartan or telmisartan combined with HCTZ on 24‐hour BP control compared with previous treatments in patients with essential hypertension. ABPM was used to record each patient's BP over 24 continuous hours at baseline and at the end of treatment to measure the effects of telmisartan‐based therapy. To avoid measurement bias, the study employed a remote data transfer design such that the investigators were blinded to the 24‐hour ABPM data.

Physician Training

A key component of this trial was the attendance at investigator meetings of all participating clinicians and their key staff before study initiation. The meetings provided an opportunity for meticulous review of the trial protocol and training in techniques such as ABPM and appropriate completion of study documents. In addition, investigators were exposed to careful reviews justifying and explaining the rationale for treating hypertension and achieving recommended BP targets.

Study Patients

Patients were considered for study enrollment by their practitioners if they fulfilled the following criteria: uncontrolled, treated stage I or II essential hypertension, defined as diastolic office BP 90–109 mm Hg or systolic office BP 140–179 mm Hg; 18 years or older; and not of childbearing potential. Patients were excluded from the study if they had any of the following: known hypersensitivity to ARBs or thiazide diuretics; history of angioedema associated with use of an angiotensin‐converting enzyme (ACE) inhibitor; history of hypertensive encephalopathy, stroke, or transient ischemic attack within the past 6 months; history of coronary heart disease events within the past 3 months; congestive heart failure; or clinically significant hepatic or renal disease.

After the initial visit and baseline measurements, the following medications were not allowed during the remainder of the study: ACE inhibitors and ARBs (other than telmisartan); β blockers (ophthalmic preparations were allowed); calcium channel antagonists; peripheral α blockers and central a agonists; diuretics; antiarrhythmic medication, including digoxin use within 5 days of study entry; phenothiazines, monoamine oxidase inhibitors, and tricyclic antidepressants (chronic stable use of serotonin uptake inhibiting agents was allowed); and amphetamines or amphetamine derivative agents.

The protocol was approved by the appropriate institutional review boards and was conducted in accordance with the ethical principles originally described in the Declaration of Helsinki. All patients provided signed informed consents before enrolling in the study.

Study Plan

The study schedule consisted of five to seven office visits over a 6–10‐week period, depending on the number of drug titrations required for each patient. All clinical visits occurred between 6 and 10 a.m. The initial screening visit included conventional measurement of seated office BP and BP medication history. Only patients currently receiving single‐agent antihypertensive therapy or two‐drug fixed combinations (most commonly with a diuretic as the second agent) were eligible for enrollment. While patients continued to take their antihypertensive treatment, a 24‐hour period of ABPM was conducted. The following morning, the patients returned to the office for completion of the ABPM procedure. Previous antihypertensive medication was then discontinued and immediately replaced by telmisartan 40 mg once daily. After 2 weeks, study practitioners would then up‐titrate to telmisartan 80 mg and then, after a further 4 weeks, to telmisartan HCTZ (telmisartan 80 mg/HCTZ 12.5 mg) depending on whether or not BP control (<140/90 mm Hg) was achieved according to the patient's office measurements. After the final titration step, patients remained on that treatment for a final 4‐week period; at the end of that time, the ABPM was repeated. As is typical in clinical trials, drugs were provided without charge to the patients. Adverse events from study entry to study exit were also evaluated and recorded.

Office Measurements

Office Bps were measured with standard mercury sphygmomanometers with appropriate cuff sizes according to American Heart Association guidelines. ⁹ Investigators were instructed to use the same BP monitor and the same observer for each patient visit, and to use the nondominant arm for all BP measurements throughout the study to optimize consistency in measurements. Bps were measured after at least 5 minutes in the examination room, during which the patient remained seated and quiet. Two seated Bps were measured at least 2 minutes apart, allowing the cuff to fully deflate between readings for accurate measurement. Bps were expressed as the mean of the two readings.

Ambulatory BP Monitoring

Ambulatory BP monitoring devices (Model 90207, SpaceLabs Medical, Issaquah, WA) ¹⁰ were used with the appropriately sized cuff and bladder. The units were programmed to take measurements every 20 minutes throughout the 24‐hour period. With this technique, the first five BP measures appeared on the device's display screen, but all subsequent measures were blinded. If the recording device was unable to obtain BP data at a particular time point, the measurement was repeated within 1–2 minutes according to the standard algorithm of the ABPM unit.

The 24‐hour ABPM procedure began at 8 a.m. ± 2 hours on a normal workday. In order for the 24‐hour test to be considered successful, at least 80% of total readings for the 24‐hour period had to be valid and no more than two consecutive hours were allowed to lack valid readings. An hour was considered valid if at least one valid reading was captured during that hour. Patients who did not have a successful ABPM at baseline were offered the opportunity to repeat the 24‐hour procedure. Each patient's mean 24‐hour ABPM systolic and diastolic Bps were calculated by averaging the valid readings over each 24‐hour period. Values beyond the first 24 hours were truncated.

Data from the ABPMs were downloaded to a central site where initial editing of the data was performed by computer, and then the entire record was reviewed by a trained technician. Each study practitioner subsequently received a report outlining the summary and hourly BP readings for each patient's successful 24‐hour ABPM procedure.

Data Analyses

The study end points included the changes in mean 24‐hour ABPM systolic and diastolic Bps from baseline (visit 1) to study exit (visit 3 or visit 4); changes in office diastolic and systolic Bps; and BP control rates. To be considered controlled at study exit by ABPM, the 24‐hour diastolic BP average had to be <80 mm Hg, and the systolic BP <130 mm Hg; and for office BP, <90 and <140 mm Hg, respectively. Only those patients with successful baseline and end‐of‐treatment ABPM procedures were included in the analyses.

Discrete variables, such as BP control rates, were summarized by frequencies and percentages and compared by group using the chi‐square test. Continuous variables were summarized by descriptive statistics and compared using analysis of variance if the data were normally distributed; if the data were not normally distributed, the Kruskal‐Wallis test was used. Adjusted differences for continuous efficacy variables were calculated using an analysis of covariance, with baseline values as a covariate and treatment group as a factor in the model. If the data were not normally distributed, the Wilcoxon rank‐sum test was used for the comparison of the groups. Within each group, the hypothesis of no mean change from baseline was tested using a paired t test, or Wilcoxon signed rank test if the data were not normally distributed. The analyses were performed using SAS software, version 8.0 (SAS Institute, Cary, NC). For all analyses, p<0.05 was considered statistically significant.

RESULTS

A total of 755 patients completed the protocol, of whom 675 successfully underwent a 24‐hour ABPM procedure at baseline (on previous mono‐therapy or two‐drug therapy) and during treatment with telmisartan‐based therapy. The principal characteristics of the 675 patients with ABPM data are summarized in Table I. The mean age of the patients was 59 years, with approximately two thirds younger than 65. Reflecting a typical practice‐based population, women patients outnumbered men in this cohort. The majority of patients were white, although almost 12% were African American. The mean body mass index for the patients in this study was slightly >30 kg/m². In fact, almost half the patients in the study (45.4%) satisfied the criterion for obesity. The mean baseline (on previous therapy) office BP for the patients overall was 150/89 mm Hg.

Table I.

Baseline Characteristics of Previously Treated Patients (N=675)

Characteristic	Value
Age at enrollment (yr)
Overall	58.8±12.7
<65	446 (66.4)
≥65	226 (33.6)
Gender
Male	293 (43.7)
Female	378 (56.3)
Race
Caucasian	520 (77.2)
African American	78 (11.6)
Hispanic	31 (4.6)
Asian	37 (5.5)
Other	8 (1.2)
Body mass index (kg/m2)
Overall	30.2±6.3
<25	141 (21.1)
25–29	224 (33.5)
≥30	303 (45.4)
Office SBP (mm Hg)	149.9±14.3
Office DBP (mm Hg)	89.1±9.5
Data are presented as mean ± SD or n (%). SBP=systolic blood pressure; DBP=diastolic blood pressure

Baseline BP Values

The baseline ABPM and office Bps for each of the patient groups (defined on the basis of the drug class being taken at the time of the baseline measurements) are shown in Table II. The data are shown first for the patients as a whole; and then are shown separately for those patients who, after discontinuing their previous therapies, remained on telmisartan monotherapy throughout the study (and thus had their final ABPM procedure on that treatment); and for those patients who received combination therapy (telmisartan plus HCTZ by the end of the study and, thus, had their final ABPM on that therapy). In each of the patient groups, regardless of whether they received monotherapy or combination therapy, the differences between ABPM and office values are highly significant (p<0.01) for both systolic and diastolic BP measurements. It is also noteworthy that the baseline office and ABPM values for both systolic and diastolic Bps were higher for those patients who required combination therapy as compared with those who remained on monotherapy; the one exception to this finding was for the group of patients previously being treated with diuretic monotherapy in whom there was no difference in baseline office or ABPM values between those individuals who remained on monotherapy or were treated with combination therapy. For the patients as a whole, the mean baseline values (on previous treatment) were in the hypertensive ranges for both office (≥140/90 mm Hg) and ambulatory (≥130/80 mm Hg) BP measurements. However, as shown later, a small proportion of patients entering the study on previous antihypertensive therapy had Bps that were already in the controlled range.

Table II.

Baseline Ambulatory Blood Pressure (BP) Monitoring and Office BP Measurements, by Prior Treatment Drug Class

			Prior Treatment Drug Class*
Baseline BP (mm Hg) (mean± SD)	ACEI	ARB	β Blocker	CCB	Diuretic	ACEI + Other**	ARB + Diuretic
All Patients (n)	169	47	50	103	37	33	183
Systolic
ABPM	135.3±14.9	132.6±13.8	139.3±14.8	136.9±11.9	136.4±12.1	140.5±16.5	132.4±13.7
Office	146.9±14.6	150.3±14.1	156.7±16.8	150.3±13.1	152.0±13.8	153.4±12.8	150.1±14.4
Diastolic
ABPM	78.6±9.7	75.8±10.1	79.4±10.5	77.1±8.8	77.1±9.4	80.0±10.9	75.8±10.4
Office	88.8±9.2	90.3±10.3	91.8±10.2	87.8±9.6	86.7±10.6	91.9±10.1	88.5±8.9
Monotherapy † (n)	93	21	27	52	17	9	89
Systolic
ABPM	132.1±12.8††	129.6±15.2	131.8±10.9††	131.7±10.5††	137.0±9.5	137.2±17.8	128.4±10.8††
Office	143.7±14.6††	146.4±13.3	153.5±15.2	146.4±12.1††	150.8±12.8	150.9±15.2	145.4±12.4††
Diastolic
ABPM	77.1±9.1††	76.1±11.2	74.5±8.1††	75.8±7.1	76.6±8.4	77.5±8.2	73.5±9.5††
Office	87.8±9.1	87.6±12.1	89.3±8.8	87.2±10.0	84.1±10.8	89.5±9.4	87.7±8.8
Combination † (n)	75	26	23	50	20	22	90
Systolic
ABPM	139.4±16.4††	135.0±12.2	148.2±14.1††	142.0±11.2††	135.9±14.2	142.9±16.4	136.9±14.9††
Office	151.1±13.7††	153.5±14.2	160.5±18.1	154.6±12.6††	152.9±14.9	153.7±12.0	154.9±14.6††
Diastolic
ABPM	80.6±10.3††	75.5±9.3	85.2±10.2††	78.5±10.2	77.6±10.3	81.1±12.2	78.0±10.8††
Office	90.0±9.1	92.4±8.3	94.7±11.1	88.7±9.2	88.9±10.2	91.8±9.6	89.6±8.9
ABPM=ambulatory BP monitor; ACEI=angiotensin‐converting enzyme inhibitor; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; *33 patients previously on other combination therapies not included; **16 patients previously on ACEI + diuretic; 17 patients previously on ACEI + other antihypertensive; †final treatment was defined as the treatment at the end of study. Monotherapy included all patients who ended the study with telmisartan 40 mg or 80 mg. Combination included all patients who ended the study with telmisartan + hydrochlorothiazide. Final treatment assessment data were missing for 10 patients; †† p<0.05 comparing monotherapy group vs. combination group

Changes in BP During the Study

For each of the individual treatment groups, the changes in systolic and diastolic Bps measured by ABPM or office readings following the change in treatment to telmisartan‐based therapy are shown in the Figure(A and B). In addition, the findings in those patients who remained on telmisartan monotherapy during the study, and in those who received combination treatment, are detailed in Table III. For the patients as a whole, the changes in systolic and diastolic Bps were significant (p<0.03). However, for patients who received monotherapy or combination therapy, the changes in systolic and diastolic Bps as measured by ABPM were significant (p<0.02) except for those who were previously treated with a combination therapy of an ACE inhibitor and other therapy. Additionally, there were no significant changes (p>0.05) in diastolic BP as measured in the office (among the monotherapy group) and in systolic BP as measured in the office (among the combination therapy group) for those patients who were previously treated with a combination therapy of an ACE inhibitor and other therapy. Of note, the decreases in both systolic and diastolic Bps as measured by office readings were significantly greater than those measured by ABPM (p<0.04) with the exception of the change in diastolic BP among those patients who were previously treated with a diuretic monotherapy. As might be expected, the BP changes in patients previously on combination therapies were less than those in patients previously receiving single‐agent therapy.

Figure.

Changes during telmisartan‐based therapy in systolic blood pressure (BP) (SBP) and diastolic BP (DBP), as measured by (A) ambulatory BP monitoring (ABPM) or (B) office readings, grouped according to previous treatment regimens. Values are mean ± SEM. ACE=angiotensin‐converting enzyme; ARB=angiotensin receptor blocker; CCB=calcium channel blocker

Table III.

Change in Blood Pressure (BP) As Measured by ABPM and Office BP Measurements, by Prior Treatment Drug Class

			Prior Treatment Drug Class*
Change in BP (mm Hg) (Mean± SEM)	ACEI	ARB	β Blocker	CCB	Diuretic	ACEI + Other**	ARB + Diuretic
All Patients (n)	169	47	50	103	37	33	183
Systolic
ABPM	−8.7±12.2	−9.6±10.8	−11.9±11.1	−7.3±13.5	−13.2±9.8	−6.1±14.5	−5.5±11.6
Office	−14.3±15.2	−17.5±16.0	−22.8±17.9	−17.2±14.3	−20.8±17.3	−12.3±18.5	−15.9±15.1
Diastolic
ABPM	−4.9±7.2	−5.3±7.3	−5.2±7.6	−4.2±7.8	−7.2±5.1	−3.3±8.3	−2.4±7.4
Office	−9.5±6.4	−8.9±10.3	−10.6±9.4	−9.7±9.4	−8.6±11.3	−7.3±12.3	−8.2±8.7
Monotherapy † (n)	93	21	27	52	17	9	89
Systolic
ABPM	−7.2±10.0	−7.0±9.5	−9.2±10.2	−4.7±12.7	−13.1±8.5	−8.2±18.2	−4.7±11.0
Office	−15.3±12.8	−17.3±11.4	−28.4±15.2††	−17.9±12.2	−22.6±14.6	−21.2±12.0	−17.3±12.3
Diastolic
ABPM	−4.2±6.8	−3.9±6.5	−3.6±7.1	−3.9±6.3	−7.7±4.2	−2.8±9.0	−1.8±7.4
Office	−10.8±9.6††	−9.0±8.8	−11.9±9.9	−11.8±9.0††	−9.5±8.4	−9.4±16.7	−9.8±8.3††
Combination † (n)	75	26	23	50	20	22	90
Systolic
ABPM	−10.6±14.4	−11.6±11.6	−15.2±11.5	−9.5±13.5	−13.2±10.9	−5.7±13.6	−6.4±12.3
Office	−13.4±17.9	−17.6±19.2	−16.2±18.8††	−16.2±16.3	−19.4±19.7	−8.4±19.6	−14.4±17.3
Diastolic
ABPM	−5.7±7.7	−6.4±7.8	−7.1±7.8	−4.6±9.2	−6.8±5.8	−3.5±8.3	−2.9±7.5
Office	−7.7±9.5††	−8.8±11.5	−9.1±8.7	−7.1±9.4††	−7.9±13.4	−5.9±10.8	−6.9±9.0††
ABPM=ambulatory BP monitor; ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; *33 patients previously on other combination therapies not included; **16 patients previously on ACEI + diuretic; 17 patients previously on ACEI + other antihypertensive; †final treatment was defined as the treatment at the end of study. Monotherapy included all patients who ended the study with telmisartan 40 mg or 80 mg. Combination included all patients who ended the study with telmisartan + hydrochlorothiazide. Final treatment assessment data were missing for 10 patients; †† p<0.05 comparing monotherapy group vs. combination group

BP Control Rates

The numbers of patients whose Bps were controlled during the study (ABPM <130/80 mm Hg; office <140/90 mm Hg) are shown for each of the individual treatment groups in Table IV. Data are also shown separately for patients finishing either on monotherapy or on combination therapy. It is evident that, judged by office Bps, the control rates at baseline were relatively low (9.7%) across all the treatment groups; the control rate by ABPM at baseline was clearly higher (30%). This difference was significant (p<0.01). Since attaining control as measured by the office BP was the criterion by which patients were advanced from monotherapy to combination therapy, it is noteworthy that across all individual treatment groups, the control rate for those patients remaining on monotherapy was 91.2%. This indicates that only relatively few patients (8.8%) who should have been placed on combination therapy were not given this opportunity. As shown in Table IV, control rates in general were somewhat lower during treatment as judged by ABPM than by office readings. These data indicate that, judged by the objective (though arbitrarily set) criterion of ABPM control, clinicians in the study tended to overestimate BP values at study baseline, and then to overestimate the efficacy of treatment at the end of the study. It is also noteworthy that the highest control rate, as judged by the ABPM, among those patients remaining on monotherapy was in the subgroup who had previously been treated with single‐agent diuretic therapy.

Table IV.

Blood Pressure (BP) Control Rates Based on 24‐Hour ABPM and Office BP During Treatment, by Prior Treatment Drug Class

			Prior Treatment Drug Class*
BP Control (mm Hg) (n [%])	ACEI	ARB	β Blocker	CCB	Diuretic	ACEI + Other**	ARB + Diuretic
All Patients (n)	169	47	50	103	37	33	183
ABPM <130/80
Baseline	59 (34.9)	19 (40.4)	11 (22.0)	27 (26.2)	8 (21.6)	7 (21.2)	72 (39.3)
Final visit	93 (55.0)	34 (72.3)	23 (46.0)	56 (54.4)	27 (73.0)	14 (42.4)	112 (61.2)
Office BP <140/90
Baseline	22 (13.0)	4 (8.5)	1 (2.0)	10 (9.7)	3 (8.1)	2 (6.1)	23 (12.6)
Final visit	124 (73.4)	31 (66.0)	34 (68.0)	81 (78.6)	27 (73.0)	18 (54.5)	125 (68.3)
Monotherapy † (n)	93	21	27	52	17	9	89
ABPM <130/80
Baseline	39 (41.9)††	11 (52.4)	11 (40.7)††	19 (36.5)††	2 (11.8)	3 (33.3)	47 (52.8)††
Final visit	57 (61.3)	16 (76.2)	17 (63.0)††	36 (69.2)††	14 (82.4)	6 (66.7)	64 (71.9)††
Office BP <140/90
Baseline	17 (18.3)††	3 (14.3)	0 (0.0)	6 (11.5)	2 (11.8)	1 (11.1)	16 (18.0)††
Final visit	87 (93.6)††	16 (76.2)	27 (100.0)††	50 (96.2)††	16 (94.1)††	7 (77.8)	78 (87.6)††
Combination † (n)	75	26	23	50	20	22	90
ABPM <130/80
Baseline	19 (25.3)††	8 (30.8)	0 (0.0)††	8 (16.0)††	6 (30.0)	3 (13.6)	23 (25.6)††
Final visit	35 (46.7)	18 (69.2)	6 (26.1)††	19 (38.0)††	13 (65.0)	7 (31.8)	45 (50.0)††
Office BP <140/90
Baseline	5 (6.7)††	1 (3.9)	1 (4.4)	3 (6.0)	1 (5.0)	1 (4.5)	6 (6.7)††
Final visit	36 (48.0)††	15 (57.7)	7 (30.4)††	30 (60.0)††	11 (55.0)††	10 (45.5)	45 (50.0)††
ABPM=ambulatory BP monitor; ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; *33 patients previously on other combination therapies not included; **16 patients previously on ACEI + diuretic; 17 patients previously on ACEI + other antihypertensive; †final treatment was defined as the treatment at the end of study. Monotherapy included all patients who ended the study with telmisartan 40 mg or 80 mg. Combination included all patients who ended the study with telmisartan + hydrochlorothiazide. Final treatment assessment data were missing for 10 patients; †† p<0.05 comparing monotherapy group vs. combination group

Treatment Tolerability

The use of telmisartan‐based therapy in patients who entered the study receiving treatment with other antihypertensive agents was associated with good tolerability. As reported previously, ⁶ of the patients who originally entered the study, 7% discontinued due to noncompliance with the protocol, 9% due to withdrawal of consent, 3% were lost to follow‐up, and 6% discontinued due to adverse events. As shown in Table V, very few individual adverse events occurred with a frequency of >1%. There were too few adverse events to determine whether there were differences in their frequency in patients in the differing subgroups of previous therapy.

Table V.

Frequency (>0.2%) of Drug‐Related Adverse Events Among Previously Treated Patients (n [%])

Patients studied	675 (100)
Patients with an adverse event	107 (15.9)
Patients with a drug‐related adverse event	41 (6.1)
Drug‐related adverse events
Dizziness (excluding vertigo)	12 (1.8)
Fatigue	10 (1.5)
Headache	6 (0.9)
Constipation	2 (0.3)
Muscle cramps	2 (0.3)
Lower limb edema	2 (0.3)
Rash (not otherwise specified)	2 (0.3)
Somnolence	2 (0.3)
Urticaria (not otherwise specified)	2 (0.3)
Weakness	2 (0.3)

DISCUSSION

This study has shown that therapy based on the ARB telmisartan can achieve high rates of BP control in patients previously treated with a variety of antihypertensive agents. Earlier studies have shown that this type of therapy, either with telmisartan or other agents in its class, was very effective at controlling BP as monotherapy or in combination with the diuretic HCTZ. ¹¹ , ¹² , ¹³ The present study has provided an opportunity to test this efficacy by comparing it with previously administered therapies with different types of widely used antihypertensive agents. An essential part of the study design of this investigation was the use of ABPM. This rigorous method eliminates placebo effects ⁷ , ⁸ so that BP differences between previous treatments and a new regimen provide a true measure of relative treatment effects.

The overall control rates for this simple regimen were impressive: by office BP criteria (<140/90 mm Hg) they were 71%; and by ABPM criteria (mean 24‐hour BP average <130/80 mm Hg), they were 57%. This small discrepancy in results between the two methods could be at least partly explained by our use of the very rigorous 130/80 mm Hg criterion for ABPM; this is a somewhat arbitrary value, ¹⁴ and obviously a less stringent cutoff would have produced higher control rates by ABPM.

Even so, the concordance between the two methods was sufficiently close to provide confidence in the validity of the office BP measurements. Indeed, it is noteworthy that the use of the blinded end point provided by the ABPM data in this study provides important confirmation that the clinical observations reported previously in community‐based trials ¹² were substantially valid and not the result of investigator bias.

A further outcome of this trial, conducted in the community setting chiefly by primary care physicians, was the demonstration of their willingness to carefully follow the protocol of the clinical trial. In particular, the study required that patients whose Bps were not controlled by the higher dose of monotherapy be advanced to treatment with the combination of telmisartan with HCTZ. This decision was based on conventional office readings (rather than ABPM), and by this criterion over 90% of patients remaining on monotherapy by the end of the study were appropriately controlled. This willingness of clinicians to follow a structured treatment plan, clearly more so than in routine practice ¹ or as shown in previous community‐based trials, ¹⁵ could be due to the fact that physicians were compensated for conducting the study; but it also speaks to the scientific and educational value of the detailed investigator meetings conducted immediately before initiation of the trial.

Our findings, in fact, allow two conclusions of practical importance. First, that busy practicing physicians are willing to follow treatment algorithms if they are given adequate opportunities to fully explore their logic and make a commitment to them; and second, that practice‐based clinical trials, if conducted with the same attention to detail as with classical clinical trials, can provide data—in this case, validated by the rigorous ABPM measurements—that are scientifically credible and clinically useful.

It should be noted, as in a previous report, ¹² that the greatest BP reduction occurred in those patients previously being treated with a diuretic. This is not really surprising, for in the volume–vasoconstriction construct of hypertension, high BP is sustained by an increase in intravascular volume (low‐renin hypertension), or excessive vasoconstriction mediated through the renin–angiotensin system (high‐renin hypertension), or both (medium renin). So, patients not responding well to monotherapy with a diuretic could be expected to do better when treated with a blocker of the renin–angiotensin system (and vice versa).

It is not surprising that replacing one treatment regimen that had not been particularly efficacious by another would result in a fall in BP. What is less easy to explain, though, is how when substituting a drug like telmisartan for drugs with similar characteristics—in particular, other ARBs—ACE inhibitors or even combinations of these drugs with diuretics, there was still a reduction in BP. There appear to be three possible responses to this question.

First, these results could be explained by the performance of the patients. Entering a clinical trial, and being compelled to go through the exercise of reading and understanding a detailed informed consent document, provides a helpful education for patients planning on joining a study such as this. And, beyond that, the formality of this process gives many patients a sense of obligation to their physicians, resulting in a more careful adherence to treatment requirements than might be the case in usual clinical practice. The second explanation for these unexpected results could be explained by the performance of the physician investigators. As discussed earlier, physicians who have attended an investigator meeting are more likely to understand the logic behind setting clear goal levels for BP therapy; moreover, a trial such as this creates the type of professional peer pressure that compels physicians to closely follow the protocol's treatment algorithm so as to optimize results. Finally, there may be explanations related to the drug itself. Telmisartan is a powerful ARB with a long duration of action. It has been shown previously to be more efficacious than some other drugs in decreasing BP ⁵ , ¹⁶ and, in some cases, in the present study it is likely that telmisartan was titrated more aggressively than the agents that preceded it.

One of the recommended uses of ABPM is to determine whether apparently hypertensive patients are exhibiting the so‐called white coat effect by which their Bps are atypically high in the presence of a physician. ¹⁷ Usually this problem has been considered in the context of the initial diagnosis of hypertension, ⁶ , ¹⁸ but the present study emphasizes that this effect can also be observed in patients already receiving antihypertensive therapy. According to the conventional office measurements, fewer than 10% of patients had their Bps controlled on previous therapy; by ABPM, close to 30% had their Bps controlled. Still, during the course of the trial, the differences between Bps measured by the office and ambulatory techniques actually diminished, indicating that there is an attenuation of the white coat effect across multiple visits to the office. As a practical matter, this suggests that patient familiarization with the medical office and its personnel can have the useful effect of improving the accuracy of BP readings.

It must be acknowledged that an open‐label study such as this, despite the use of a scrupulously blinded end point, is best regarded as an effectiveness or naturalistic trial. The patient cohorts, with women outnumbering men, and with almost half meeting the body mass index definition of obesity, are highly typical of patients being treated for hypertension in American community‐based practices. Trials such as this not only provide insight concerning efficacy, but also cast a strong light on how a particular treatment can function in the real world. In particular, it provides pertinent information on the physician–patient interaction, and it can provide a basis for recommendations to improve the care of a particular condition—in this case, hypertension—in everyday practice.

CONCLUSIONS

An ARB, telmisartan, alone or in combination with HCTZ, is a well tolerated and highly efficacious antihypertensive agent. In addition, we have demonstrated that a formalized and structured approach to treating a common chronic condition can enhance the performance of both physicians and patients in their joint goal of achieving treatment goals. In fact, translating the approaches used in this study into recommendations for routine practice should have the effect of improving clinical outcomes across a large part of the community.

Disclosure: This study was supported by a grant from Boehringer‐Ingelheim Pharmaceuticals, Ridgefield, CT. Drs. Weber, Giles, Bakris, Neutel, and White have served as consultants to Boehringer‐Ingelheim Pharmaceuticals or have given talks under its sponsorship. Drs. Weber, Smith, and Neutel also have interests in Integrium, a contract research organization that managed the trial. In addition, Dr. Bakris is a consultant for AstraZeneca, AusAm, Abbott, Alteon, Biovail, Boehringer‐Ingelheim, Bristol‐Myers Squibb/Sanofi‐Aventis, Forest, GlaxoSmithKline, Merck, Novartis, Lilly, Takeda, and Wyeth, and is a member of the Speakers' Bureau for AstraZeneca, Abbott, Alteon, Biovail, Forest, GlaxoSmithKline, Merck, Novartis, and Wyeth. Dr. Weber provides speaking and consulting services for Novartis, Bristol‐Myers Squibb, Merck, Pfizer, Sanofi‐Aventis, and Sankyo. Dr. Smith and Dr. Neutel provide speaking or consulting services for Novartis, Bristol‐Myers Squibb, Merck, Pfizer, Sanofi‐Aventis, and Sankyo. Dr. Giles and Dr. White provide speaking or consulting services for Novartis, Bristol‐Myers Squibb, Pfizer, Sanofi, and Sankyo. Dr. Davidai is an employee of the medical department at Boehringer‐Ingelheim in Ridgefield, CT. The authors had complete access to the data, supervised the analyses, and are fully responsible for the content of this manuscript.