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Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9,048), or lisinopril 10-40 mg/d (n=9,054) in a randomized double-blind hypertension trial. Participants were hypertensives age t55 with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mmHg (27% control) to 134/76 mmHg (chlorthalidone, 68% control), 135/75 mmHg (amlodipine, 66% control), and 136/76 mmHg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. A majority achieved BP control in each randomized group--a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP<140/90 mmHg in a majority of patients.
More than 70 million Americans–nearly one in three adults–have hypertension; its prevalence increases with age.1,2 It is a major risk factor for coronary heart disease (CHD), heart failure (HF), stroke, and renal failure. It is reasonable to infer that improved detection, treatment, and control of elevated blood pressure (BP) were important contributors to the 64% decline in age-adjusted cardiovascular mortality rates that has occurred since 1963.2 But aging of the population, the epidemic of obesity, and longer survival with hypertension have all led to an actual increase in the prevalence of hypertension–the most common primary diagnosis recorded by physicians in the US and the principal diagnosis for 38 million office visits during 2001.3
Extensive public health efforts aimed at identifying, evaluating, and treating individuals with arterial hypertension have significantly improved BP control rates (<140/90 mmHg) among US adults with hypertension in recent years, from 29% in 2000 to 37% in 2004, but for the majority, BP remains uncontrolled, especially among older individuals and some minorities.4 These low BP control rates have been difficult to explain, given the number of apparently well-tolerated antihypertensive agents5 and the periodic publication of consensus guidelines.5-8 A number of potential barriers to BP control have been proposed, including limited access to care, choice of antihypertensive drugs, provider practice patterns, and patient adherence. Recent reports strongly suggest that a major factor in inadequate BP control is the provider's failure to increase doses or numbers of antihypertensive medications in the management of patients with uncontrolled BP.9, 10
The ALLHAT trial, which was conducted in diverse North American demographic and medical settings, found that treatments based on an angiotensin converting enzyme (ACE)-inhibitor (lisinopril, L), a calcium channel-blocker (CCB, amlodipine, A), or an α-blocker (doxazosin, D) were not superior to thiazide-type diuretic (chlorthalidone, C) based treatment in preventing CHD, stroke, and renal complications of hypertension. Chlorthalidone was superior in preventing HF (compared to A, L, or D), combined cardiovascular events (compared to L or D), and stroke (compared to D and, among Blacks, L).11, 12
We have previously reported that BP was controlled to <140/90 mmHg in two-thirds of ALLHAT participants, and concluded that it is likely that the vast majority of people with hypertension could achieve BP<140/90 mmHg with the antihypertensive medications available today.10 This report describes BP control in ALLHAT within and across randomized treatment groups over time, the relationship of BP control to the numbers and doses of drugs used, and factors that predict BP control within each randomized group. The doxazosin arm was terminated early and is not included in this report.11
The rationale and design of ALLHAT have been published.13, 14 Briefly, eligible participants were hypertensive men and women 55 years or older with at least one additional risk factor for CHD [previous myocardial infarction or stroke (>6 months), other atherosclerotic vascular disease, left ventricular hypertrophy, type 2 diabetes, current cigarette smoking, and high density lipoprotein-cholesterol<35 mg/dL]. For untreated participants (and those treated for less than 2 months), BP inclusion criteria were average SBP≥140 and/or DBP≥90 mmHg but ≤180/110 mmHg at two screening visits. Treated participants (1-2 antihypertensive drugs) were required to have BP≤160/100 mmHg at the first screening visit and ≤180/110 mmHg at the second.13, 15 Participants (n=33,357) were recruited in 623 centers in North American16, 17 and were randomly assigned to chlorthalidone, amlodipine, or lisinopril. To maximize statistical power, 1.7 times as many participants were assigned to the chlorthalidone treatment arm than the alternative treatment arms (originally three, including doxazosin).18, 12, 13 The treatment goal was BP<140/90 mmHg. All participants signed an informed consent form, and all centers received institutional review board approval.
Blinded study drugs were titrated through three dosage levels: 12.5, 12.5 (sham titration), and 25 mg/d for chlorthalidone; 2.5, 5, and 10 mg/d for amlodipine; and 10, 20, and 40 mg/d for lisinopril. If BP goal was not met on maximum tolerated dosage of the blinded medication, open-label Step 2 agent [atenolol (25–100 mg/d), reserpine (0.05–0.2 mg/d), or clonidine (0.1–0.3 mg twice/day)] could be added and increased until goal was reached. If goal BP was still not achieved, an open-label Step 3 agent, hydralazine (25–100 mg twice/day), could be added. After initial titration visits, participants were seen every 3 months during the first year and every 4 months thereafter. This report describes the medication and BP status of participants at randomization, 6 months, annual follow-up visits, and the last treatment visit in the six-month period immediately prior to the trial's close-out.
Non-study open-label drugs could be added to or substituted for Step 2 or 3 open-label medications to improve tolerance or BP control. However, use of open-label medications from one of the blinded classes of drugs could be used only if SBP was >160 mmHg and/or DBP was >100 mmHg after maximum tolerated titration of blinded and open-label study drugs, or a compelling indication, such as HF, arose for one of the blinded drug classes.
Control of BP and adherence to assigned blinded medication were two of six key clinic performance measures monitored throughout the trial. A clinic-specific performance profile indicated how each clinic compared with regional and overall study performance. These reports were monitored by Regional Physician Coordinators, who provided counseling to clinic investigators as appropriate regarding means to improve performance.19
Blood pressure measurement technique and definition of visit BP have been described previously.10 Mean BP levels and percent-control (<140/90 mmHg) at baseline and follow-up were calculated for 18 major subgroups within each treatment group. Use of additional drugs, average Step 1 dose, percent remaining on Step 1 drug, and percent controlled on different number of drugs at follow-up were also tabulated for these subgroups. Multiple logistic regression analyses were performed to assess the independent influence of baseline variables on BP control at year-3 according to randomized treatment group.
Detailed baseline results have been published.15 Briefly, the three randomized treatment groups were similar. Mean age was 67 years, 47% were women, 35% black, and 22% cigarette smokers. Thirty-six percent had a history of diabetes, 26% had pre-existing CHD, and 90% were on 1-2 antihypertensive drugs prior to enrollment. At the first screening visit, mean BP was 145/83 mmHg (159/91 mmHg for the 10% untreated); the BP control rate was 27%.
During follow-up, mean SBP/DBP decreased and control rates increased in all three groups (Table 1). Among participants who attended a treatment visit in the last 6 months of follow-up, mean BP was lower than at baseline by 12.8/8.3 mmHg, 12.2/9.1 mmHg, and 11.9/8.5 mmHg for C, A, and L, respectively. The average Step 1 dose prescribed to participants increased steadily over time, as did the average number of drugs prescribed (Table 1); after 60 months, average doses of step 1 medication were 19.7 mg, 7.9 mg, and 29.9 mg for C, A, and L, respectively. Blood pressure control (<140/90 mmHg) increased in all three groups, to 68%, 66%, and 61% for C, A, and L, respectively, at year-5 (Table 1) and was controlled in 69-73% at the last treatment visit. Diastolic BP control was achieved more often than systolic (92% versus 67%, overall).10 Of the 32-39% not controlled across treatment groups at year-5, the majority (53.5%) had BP<150/95 mmHg (54.1% C, 57.6% A, 49.0% L) (data not shown).
The year-3 mean BP, average Step 1 drug dose, mean number of antihypertensive drugs prescribed, and percentage with controlled BP are presented in Table 2 for major subgroups defined by demographics and CVD risk factors. Regardless of treatment assignment, BP control tended to be better in men, nonblacks, non-diabetics, younger participants (<65 years), those with ASCVD, BMI<30 kg/m2, not on antihypertensive drugs prior to enrollment, and with eGFR≥60 mL/min/1.73m2. Younger participants, non-diabetics, blacks, the obese, those without ASCVD, and those with eGFR≥60 had higher DBP than their complements. Men and participants with ASCVD were on a slightly higher mean number of drugs compared with their complements and had better BP control rates. Diabetics, non-smokers, the obese, those with prior hypertension treatment, those with eGFR<60, and blacks assigned lisinopril had poorer BP control than their complements despite a higher average number of antihypertensive drugs.
The number and percent of participants on their assigned Step 1 drug and on one or more drugs are presented in Table 3 for major subgroups, according to the number of drugs prescribed. The large majority of participants were on one or two antihypertensive drugs in all three treatment groups (84/82/74% in C/A/L). However, a significantly larger proportion of those assigned L (compared to C or A) was on three- or four-drug regimens (p<0.001).
Table 4 shows proportions of participants with controlled BP over time according to the number of prescribed antihypertensive agents, by race. At 12 months, 39% of participants were controlled on monotherapy (41%, 37%, and 36% in C, A, and L, respectively). This number decreased to 26% by year-5 (C, 28%; A, 24%; L, 24%) with 4% requiring 4+ drugs to achieve BP control (3%, 4% and 6% in C-, A-, and L-based treatment, respectively). Only 49% of participants were controlled on less than 3 drugs at year-5; the proportion controlled was significantly higher for C (52%) than A (50%; p<0.05) or L (42%; p<0.01). Similar trends were seen for black and nonblack participants, though black participants were less likely than nonblack to be controlled on less than 3 drugs. At year-5, 45% of black participants were controlled on one or two drugs compared with 51% of nonblack participants (p<0.001); the proportion controlled was significantly higher for C (black, 50%; nonblack, 54%) compared with L (black, 33%, p<0.001; nonblack, 46%, p<0.001) but not compared with A (black 46%, p=0.056; nonblack, 52%, p=0.121).
Table 5 presents data on BP and antihypertensive drug use at year-5 by race. Mean BP was <140/90 mmHg and control rates exceeded 50% in all three drug groups in both black and nonblack participants. However, BP control was less in black compared with nonblack (61% vs. 68%, p<0.001), with greater differences seen in L (54% vs. 65%, p<0.001) than C (64% vs. 70%, p<0.001) or A (62% vs. 68%, p<0.001). This despite the fact that mean number of drugs was higher in blacks compared with nonblacks in L (2.27 vs. 2.04, p<0.001) and similar in A (2.01 vs. 1.97, p=0.31) but not in C (1.86 vs. 1.93, p=0.02). A small percentage of blacks and nonblacks (10% and 6%, respectively) had SBP≥160 mmHg, including 14% blacks on L compared with 8% on C. Among 40% blacks and 32% nonblacks with uncontrolled BP, about half had SBP<150 mmHg. The most common add-on agent for both race subgroups and all treatment groups was atenolol (21-29%), followed by hydralazine (8-22%). Among C participants, 25% of blacks and 35% of nonblacks were prescribed atenolol. Among blacks, 25% of L participants received a diuretic and 17%, a CCB. Among nonblacks, a diuretic was prescribed for 22% of A participants and 21% of L.
Figure 1 presents results from logistic regression analyses of baseline factors related to BP control at year-3. The patterns were similar across treatment groups, though there were some notable differences. Control of BP with C was superior to L and similar to A in all subgroups. Factors that were significantly related to lesser BP control in all three treatment arms included higher baseline SBP, older age, black race, diabetes, prior use of BP medications, and eGFR<60 mL/min/1.73m2. Blacks had less BP control compared with nonblacks even after controlling for other baseline factors examined in logistic analyses, and the relative odds of BP control (black/nonblack) was significantly lower among A than C participants (A/C interaction OR=0.911, p<0.01) and among L than C participants (L/C interaction OR=0.895, p<0.001). Additional logistic models including years of education and continuous variables for BMI, BMI2, and eGFR, with remaining Figure 1 characteristics, did not explain the higher risk of uncontrolled BP for black participants. Among C and A participants, a BMI ≥30 kg/m2 was significantly related to lesser BP control, but BMI (obese/non-obese) by treatment (A/C and L/C) interaction terms were not statistically significant. When considered as continuous measures, body mass index (BMI) and its square did not significantly predict BP control. Estimated glomerular filtration rate (eGFR) as a continuous variable was a statistically significant predictor of better BP control with increasing eGFR (OR: 1.0025; 95% CI, 1.0010-1.0040). Males had significantly better BP control than females in the L group (p<0.001). However, the test for drug by sex interaction was not statistically significant. The presence of ASCVD, LVH by electrocardiogram, and current smoking status were not significantly associated with BP control status at year-3.
This paper examined BP control and its determinants within and across randomized treatment groups in the largest blinded hypertension treatment trial of major morbidity and mortality endpoints. Our principal findings were: 1) BP control can be achieved in most patients with commonly available, affordable medications; 2) better BP control is achieved with a thiazide-type diuretic as step 1 drug both in a setting of monotherapy and with other drugs added, especially when compared with an ACE-inhibitor-based treatment; 3) lesser BP control in blacks could not be explained by baseline demographic or clinical characteristics.
By design, the trial included large numbers in all major subgroups defined by demographic characteristics and co-morbidities.12, 15, 20-22 In these participants, mean BP was reduced overall to ≤140/80 mmHg by year-1 and to ≤136/76 mmHg by year-5. Percent at BP goal (<140/90 mmHg) improved from 27-28% on prior therapy at baseline to ≥50% in all three treatment groups by year-1 and ≥60% by year-5. BP was controlled in more than 50% of participants in all major subgroups in each randomized treatment group by year-3, including blacks randomized to lisinopril, who had the lowest drug/subgroup control rate.
Although standardized training in BP measurement using mercury sphygmomanometers was delivered to clinic staff members, terminal digit preference for “0” was frequent, but did not differ across randomized treatment groups. Digit preference may have considerable impact on a performance measure that defines BP control as ≤140/90 mmHg (rather than <140/90)—a definition of BP control which has been used by others, such as HEDIS. 23 In ALLHAT, the overall percent of participants with BP≤140/90 mmHg was 8% greater at year-1 than the percent with BP<140/90 (63% vs 55%); at year-3, it was 8% greater (70% vs. 62%), and at year-5 it was 6% greater (72% vs. 66%). Perhaps because of BP training, these differences are less than what has been reported in a managed care setting (12.7%).24
In this older hypertensive population, SBP was reduced most in the chlorthalidone group and least in lisinopril. At year-5, BP was controlled more with chlorthalidone (67.8%) than with amlodipine (66.2%) or lisinopril (61.1%); at the end of trial follow-up, control rates were 72.9%, 72.6%, and 69.2%, respectively. Since ALLHAT was conducted in diverse clinical practice settings, control rates in clinical practice should be able to approach these levels. In fact, within the U.S. Department of Veterans Affairs, BP control rates in a diverse hypertensive population have improved from 42% in 2000 prior to the publication of the primary ALLHAT results to 67% in 2004, similar to what was achieved in ALLHAT.9, 25 Compared with 2003-2004 NHANES BP control rates (40-57% in treated hypertensive patients aged ≥60 years), this represents good BP control rates for all subgroups in ALLHAT.4
The dose of blinded medications within each drug group at year-5 averaged 20 mg per day for chlorthalidone, 8 mg per day for amlodipine, and 30 mg per day for lisinopril. These dose levels represented 75-80% of the maximum protocol allowable dose levels,13 and are higher than what is typically used in clinical practice. In addition, both effects on BP and clinical outcomes were seen with these doses, thus, establishing dose levels from which to extrapolate the outcome results of ALLHAT (reported previously).11, 12 The chlorthalidone dosage range used in ALLHAT significantly reduced events in the Systolic Hypertension in the Elderly Program (SHEP)26 and is at least as effective in lowering BP as 25-50 mg per day of hydrochlorothiazide,27 while lower doses for either diuretic have not been adequately studied in major clinical outcome trials. It is reasonable, therefore, to assume that these are the appropriate dose ranges for management of hypertension.
ALLHAT data also confirm the need for multiple antihypertensive medications to achieve BP control. Although BP entry criteria in ALLHAT were developed with the intention of recruiting a population that could potentially be controlled on one or two antihypertensive medications, only 26% of participants were below BP goal after 5 years on one drug: more (28%) in the chlorthalidone group than with amlodipine (24%) or lisinopril (24%). As expected from previous studies, more (52%) were controlled on one or two drugs with chlorthalidone therapy than with amlodipine (50%) or lisinopril therapy (42%).28 In the ALLHAT diuretic arm, which was associated with the best BP control rate (67%), 13.5% of participants were not controlled on three medications or received four or more medications and, therefore, met criteria for resistant hypertension (defined as having uncontrolled BP on three drugs in full doses, one of which is a diuretic).5 Corresponding percentages for black and nonblack participants were 14.8% and 12.8%, respectively. Because ALLHAT recruitment was intended to exclude patients with resistant hypertension, it is reasonable for physicians and others who manage hypertension, as well as patients, to expect a majority of hypertensive patients to require at least 2-3 medications to control BP.
At year-5, ALLHAT participants were prescribed an average of 2 antihypertensive drugs. Lisinopril participants were prescribed more drugs on average in blacks (2.27) than other race-drug groups, and still had the lowest BP control rates. These differential BP control rates could not be explained by clinical or demographic characteristics. Visit adherence at year-3 of follow-up was slightly better among nonblack than black participants: 85.2% of nonblack and 82.3% of black participants attended >65% of expected visits and their 32- and 36-month visits. And, BP control was better among the more adherent (63.7%) than less (54.7%), with similar findings in black and nonblack participants. However, because of potential sampling bias in such post-randomization analyses,29 differences in BP control could simply reflect a higher proportion of good adherers attending the 36-month visit rather than real differences in BP control rates.
It is possible that fewer drugs or better control rates might have been achieved if an ACE inhibitor were combined with a thiazide-type diuretic or a calcium channel blocker for management of hypertension, but to allow routine addition of the specific drug classes being compared in the trial would have confounded the interpretation of the outcome results. In the Avoiding Cardiovascular events through COMbined therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial, initial therapy with fixed dose combinations of an ACEI with either a CCB or thiazide diuretic controlled BP in 73% of participants within 6 months.30 However, this control rate may have been the result of beginning with two-drug combination therapy more than the specific combinations used.
ALLHAT results (Figure 1) show little drug heterogeneity among the three drug classes in predictors of resistance to achieving a combined SBP and DBP goal when additional antihypertensive agents are used to achieve control. These results suggest that patient characteristics associated with resistance to antihypertensive drug therapy can allow clinicians to predict when more medication may be needed. They do not support the concept that the likelihood of controlling BP with a single agent can be increased by using patient characteristics to guide the choice of the initial antihypertensive agent. Therefore, clinical outcome results from trials like ALLHAT, or other compelling indications (e.g. renal disease) should have priority when selecting among the various antihypertensive drug classes.5
Each randomized antihypertensive drug group in ALLHAT experienced high rates of BP control, as did each of the major subgroups. The thiazide-type diuretic chlorthalidone wasassociated with the best BP control rates and the ACE-inhibitor lisinopril with the least, especially in the black subgroup. This was true for both monotherapy and when additional drugs were added. Even among black participants, more than half were controlled with a lisinopril-based regimen, which did not routinely include a thiazide diuretic or a calcium channel blocker, agents that are preferred for combining with an ACE-inhibitor today. Over time, relatively few hypertensive patients can be controlled with single-drug therapy, suggesting those who care for hypertensive patients, as well as the patients themselves, should expect that multidrug therapy will often be required to achieve BP <140/90 mmHg or even lower, as has been recommended for some groups of patients.5, 31
The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Meyers Squibb (pravastatin). A complete list of members of the ALLHAT Collaborative Research Group has been published previously.11
This research was supported by Health and Human Services contract number N01-HC-35130 from the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc. (amlodipine), AstraZeneca (atenolol and lisinopril) and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer, Inc.
JNB has consulted for Novartis and Sankyo, and has received honoraria from AstraZeneca and Pfizer. WCC has consulted for Calpis, King, Myogen, Novartis, Pfizer, Roche, Sankyo, Sanofi Aventis, and Takeda, and has received honoraria from AstraZeneca, Boehringer Ingelheim, Forest Pharmaceuticals, Novartis, and Sankyo. He has also received research grants from Abbott Laboratories and Novartis. BRD has consulted for BioMarin, GlaxoSmithKline, Proctor and Gamble, and Takeda. CEF has consulted for BioMarin. RP has received researched grants from Berlex, Bristol-Myers Squibb, Ferring, Novartis, Schering Plough, Takeda, and Wyeth, and has received honoraria from Berlex, Ferring, and Pfizer. DGV has consulted for Astra-Zeneca, received honoraria from Astra-Zeneca and Merck, and has received a research grant from Boehringer Ingelheim. JTW has consulted for GlaxoSmithKline, Novartis, Pfizer, and SanofiSynthelabo, has received honoraria from GlaxoSmithKline, and has received research grants from GlaxoSmithKline and Novartis. AB, DLC, PTE, BPH, KK, GTL, TMR, RJW, and PKW have no financial interests to disclose.