ALLHAT, or the soft science of the secondary end point

The recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that the primary end point, coronary heart disease, was identical in the chlorthalidone, lisinopril, and amlodipine groups. Yet the major conclusion of this trial was that thiazide diuretics are superior in preventing 1 or more major forms of cardiovascular disease and should be preferred for first-line antihypertensive therapy. This conclusion was based solely on an analysis of secondary end points and cost. As evidenced by the dictum to "use thiazides for most patients with uncomplicated hypertension" in the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, this interpretation of ALLHAT broadly adumbrated these guidelines. Although diuretics will rightfully remain a cornerstone in antihypertensive therapy, we should remember (as we were told by the ALLHAT investigators) that secondary end points are "soft data" that should not form a basis for main conclusions or lead to a labeling of a drug class as preferred.     

Atenolol as a comparator in outcome trials in hypertension: a correct choice in the past, but not for the future?

OBJECTIVE: Twelve years after the design of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan- vs atenolol-based therapy for cardiovascular outcomes, we reviewed the literature for the effect of beta-blockers compared with initial placebo or no treatment on reduction of cardiovascular events to re-evaluate atenolol as the comparator in the LIFE study. METHODS: A literature search was conducted in September 2006 for randomized, controlled trials comparing beta-blockers with/without diuretics with placebo or no treatment in patients with hypertension and without recent cardiovascular morbidity. We calculated risk reductions for combined cardiovascular events, cardiovascular death, stroke, and coronary heart disease from groups of trials using atenolol first-line and all beta-blockers first-line. RESULTS: Five studies met the criteria. Significant risk reductions for cardiovascular events and stroke occurred in groups receiving treatment with atenolol or all beta-blockers, and for cardiovascular death in the all beta-blocker analysis. In meta-analysis of beta-blocker vs placebo or no treatment trials, risk reductions were 19% for combined cardiovascular events (95% CI 0.73-0.91, p<0.001), 15% for cardiovascular death (0.73-0.99, p = 0.037), 32% for stroke (0.57-0.82, p<0.001), and 10% for coronary heart disease (0.78-1.04, p = 0.146). CONCLUSIONS: Beta-blocker-based antihypertensive therapy significantly reduces cardiovascular risk in hypertension compared with placebo or no treatment. Atenolol was an appropriate comparator in the LIFE study. As the results of the LIFE study and other recent trials demonstrate superiority of newer agents over atenolol, this agent is not an appropriate reference drug for future trials of cardiovascular risk in hypertension.     

Cardiovascular events in elderly patients with isolated systolic hypertension. A subgroup analysis of treatment strategies in STOP-Hypertension-2

Objective: To perform a subgroup analysis on those patients in STOP-Hypertension-2 who had isolated systolic hypertension. Design and methods: The STOP-Hypertension-2 study evaluated cardiovascular mortality and morbidity in elderly hypertensives comparing treatment with conventional drugs (diuretics, beta-blockers) with that of newer ones [angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists]. In all, 6614 elderly patients with hypertension (mean age 76.0 years, range 70-84 years at baseline) were included in STOP-Hypertension-2. In the present subgroup analysis of STOP-Hypertension-2, isolated systolic hypertension was defined as systolic blood pressure at least 160 mmHg and diastolic blood pressure below 95 mmHg, in accordance with the Syst-Eur and Syst-China study criteria. In total, 2280 patients in STOP-Hypertension-2 met these criteria. In the study, patients were randomized to one of three treatment groups: “conventional” antihypertensive therapy with beta-blockers or diuretics (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or fixed-ratio hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily); ACE inhibitors (enalapril 10 mg or lisinopril 10 mg daily); or calcium antagonists (felodipine 2.5 mg or isradipine 2.5 mg daily). Analysis was by intention to treat. Results: The blood pressure lowering effect in patients with systolic hypertension was similar with all three therapeutic regimens: 35/13 mmHg in the conventional group (n = 717), 34/12 mmHg in the ACE inhibitor group (n = 724), and 35/13 mmHg in the calcium antagonist group (n = 708). Prevention of cardiovascular mortality, the primary endpoint of the study, did not differ between the three treatment groups. All stroke events, i.e. fatal and non-fatal stroke together, were significantly reduced by 25% in the newer-drugs group compared with the conventional group (95% CI 0.58-0.97; p = 0.027). This difference was attributable to reduction of non-fatal stroke while fatal stroke events did not differ between groups. New cases of atrial fibrillation were significantly increased by 43% (95% CI 1.02-1.99; p = 0.037) on “newer” drugs compared with “conventional” therapy, mainly attributable to the calcium antagonists. There were no significant differences between the three treatment groups with respect to the risks of myocardial infarction, sudden death or congestive heart failure. Conclusions: The analysis demonstrated that “newer” therapy (ACE inhibitors/calcium antagonists) was significantly better (25%) than “conventional” (diuretics/beta-blockers) in preventing all stroke in elderly patients with isolated systolic hypertension.     

Doxazosin and congestive heart failure

Doxazosin remains a commonly used antihypertensive medication, although its use has been tainted by recent findings from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT was a large, simple trial, designed in a fashion to closely mimic clinical practice as it occurs in high-risk hypertensive patients aged 55 years or older. Its goals were to determine whether the incidence of the primary outcome--a composite of fatal coronary heart disease and nonfatal myocardial infarction--differed between treatment with a diuretic (chlorthalidone) (12.5-25.0 mg/day) and treatment with each of three other types of antihypertensive drugs-a calcium-channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and a peripheral alpha-adrenergic blocker (doxazosin) (2-8 mg/day). Doxazosin was recently withdrawn from this trial after an interim analysis showed the secondary end point of combined cardiovascular disease to be 25% greater in patients on doxazosin than in those assigned to treatment with chlorthalidone. This finding was largely driven by congestive heart failure. The practicing clinician should not abandon doxazosin completely because of the ALLHAT findings, although these findings are indisputably important. These results represent an interim analysis and their application to clinical practice needs to occur carefully. A valued member of our therapeutic armamentarium need not be laid entirely to rest; rather, doxazosin should now be viewed as a secondary or tertiary antihypertensive therapy pending a more complete review of the ALLHAT data.     

Coronary heart disease prevention as the primary goal in contemporary trials in the treatment of hypertension

The prevention of coronary heart disease remains one of the greatest challenges for antihypertensive therapy. Previous trials have identified a shortfall in the protection of hypertensive patients against coronary heart disease compared with that predicted from observational studies. The present question is whether newer classes of drugs or drug combinations (calcium channel blockers, angiotensin converting enzyme inhibitors) can redress the shortfall compared with older agents (diuretics, b-blockers). However, to answer this question only two trials (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial [ALLHAT] and Anglo Scandinavian Cardiac Outcomes Trial [ASCOT]) are of sufficient size to be adqeuately powered to address this issue. ALLHAT and ASCOT have completed randomization of patients and will report on morbidity and mortality within 3 to 4 years.     

Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

BACKGROUND: Elevated blood glucose levels are reported with thiazide-type diuretic treatment of hypertension. The significance of this finding is uncertain. Our objectives were to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic, calcium-channel blocker, or angiotensin-converting enzyme inhibitor on fasting glucose (FG) levels and to determine cardiovascular and renal disease risks associated with elevated FG levels and incident diabetes mellitus (DM) in 3 treatment groups. METHODS: We performed post hoc subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) among nondiabetic participants who were randomized to receive treatment with chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n = 5034) and observed for a mean of 4.9 years. RESULTS: Mean FG levels increased during follow-up in all treatment groups. At year 2, those randomized to the chlorthalidone group had the greatest increase (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L] for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The odds ratios for developing DM with lisinopril (0.55 [95% confidence interval, 0.43-0.70]) or amlodipine (0.73 [95% confidence interval, 0.58-0.91]) vs chlorthalidone at 2 years were significantly lower than 1.0 (P<.01). There was no significant association of FG level change at 2 years with subsequent coronary heart disease, stroke, cardiovascular disease, total mortality, or end-stage renal disease. There was no significant association of incident DM at 2 years with clinical outcomes, except for coronary heart disease (risk ratio, 1.64; P = .006), but the risk ratio was lower and nonsignificant in the chlorthalidone group (risk ratio, 1.46; P = .14). CONCLUSIONS: Fasting glucose levels increase in older adults with hypertension regardless of treatment type. For those taking chlorthalidone vs other medications, the risk of developing FG levels higher than 125 mg/dL (6.9 mmol/L) is modestly greater, but there is no conclusive or consistent evidence that this diuretic-associated increase in DM risk increases the risk of clinical events.     

A family physician questions the conclusions from ALLHAT

A key Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) conclusion is that thiazide diuretics should be preferred for first-step antihypertensive therapy. ALLHAT was not a monotherapy trial, and rational drug combinations were discouraged by study design in the lisinopril limb. The ALLHAT conclusion that recommends chlorthalidone for initial hypertension therapy seems unjustified because ALLHAT was not a trial that initiated therapy for hypertension. ALLHAT was not of sufficient length to detect the poorer outcomes that are inevitable with increased rates of diabetes in the chlorthalidone limb. The heart failure subset analysis was not prospectively established. ALLHAT was not designed to make the conclusions claimed by its authors.     

Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, active, controlled clinical trial conducted to determine whether newer antihypertensive agents, including doxazosin, an alpha-blocker, differ from chlorthalidone, a diuretic, with respect to coronary heart disease (CHD) and other cardiovascular disease (CVD) events in hypertensive patients at high risk of CHD. In February 2000, the doxazosin treatment arm was discontinued, and findings through December 1999 were reported. This report includes an additional 9232 participant-years and 939 CVD events. At 623 clinical centers, patients (aged >or=55 years) with hypertension and at least 1 other CHD risk factor were randomly assigned to either chlorthalidone or doxazosin. The primary outcome measure was the combined occurrence of fatal CHD or nonfatal myocardial infarction (MI), analyzed by intent to treat; prespecified secondary outcome measures included all-cause mortality, stroke, combined CHD (fatal CHD, nonfatal MI, hospitalized angina, and coronary revascularization), and combined CVD (combined CHD, stroke, angina treated outside the hospital, heart failure, and peripheral arterial disease). Mean follow-up was 3.2 years. There was no difference in primary outcome between the arms (relative risk [RR], 1.02; 95% confidence interval [CI], 0.92 to 1.15). All-cause mortality also did not differ (RR, 1.03; 95% CI, 0.94 to 1.13). However, the doxazosin arm compared with the chlorthalidone arm had a higher risk of stroke (RR, 1.26; 95% CI, 1.10 to 1.46) and combined CVD (RR 1.20; 95% CI, 1.13 to 1.27). These findings confirm the superiority of diuretic-based over alpha-blocker-based antihypertensive treatment for the prevention of CVD.     

Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension-2. STOP Hypertension-2 Study Group

BACKGROUND: The benefits of treating hypertension in elderly diabetic patients, in terms of achieving reductions in cardiovascular morbidity and mortality, have been documented in several recent prospective trials. There has, however, been some controversy regarding the effect of different antihypertensive drugs on the frequency of myocardial infarction in this group of patients. DESIGN: STOP Hypertension-2 was a prospective, randomized, open trial with blinded endpoint evaluation. METHODS: We studied 6614 elderly patients aged 70-84 years; 719 of them had diabetes mellitus at the start of the study (mean age 75.8 years). Patients were randomly assigned to one of three treatment strategies: conventional antihypertensive drugs (diuretics or beta-blockers), calcium antagonists, or angiotensin converting enzyme (ACE) inhibitors. RESULTS: Reduction in blood pressure was similar in the three treatment groups of diabetics. The prevention of cardiovascular mortality was also similar; the frequency of this primary endpoint did not differ significantly between the three groups. There were, however, significantly fewer (P = 0.025) myocardial infarctions during ACE inhibitor treatment (n = 17) than during calcium antagonist treatment (n = 32; relative risk 0.51, 95% confidence interval 0.28-0.92); but a (non-significant) tendency to more strokes during ACE inhibitor treatment (n = 34 compared with n = 29; relative risk 1.16, 95% confidence interval 0.71-1.91). CONCLUSION: Treatment of hypertensive diabetic patients with conventional antihypertensive drugs (diuretics, beta-blockers, or both) seemed to be as effective as treatment with newer drugs such as calcium antagonists or ACE inhibitors.     

The Glycemic Effects of Antihypertensive Medications

Older antihypertensive medications are believed to be associated with metabolic disturbances, especially raised glucose levels. Owing to this, many physicians shun their use. Newer antihypertensive medications are metabolically neutral or metabolically favorable; therefore, they are looked upon favorably and are chosen as primary medications for the treatment of hypertension. Here we review the literature on the glucose effects of older and newer antihypertensive medications. We also consider what, if any, impact these metabolic effects have on cardiovascular disease outcomes. We show that the diabetogenic effects of thiazide diuretics and beta blockers are small relative to the glucose effects of angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers, and that over time, the glucose differences between older and newer medications diminish. Importantly, we show that the diabetogenic effects of older antihypertensive medications do not translate into increased cardiovascular disease risk.     

Differentialtherapie mit Calciumantagonisten

EFFICACY OF CALCIUM ANTAGONISTS: Calcium-channel blockers (CCBs) have long been recognized as potent agents for hypertensive therapy, with substantial blood pressure reduction in all age groups and races. CCBs improve endothelial function, may positively influence atherosclerosis in carotid arteries, reduce left ventricular hypertrophy, and hypertrophy of the resistance vessels, and improve arterial compliance. They do not adversely affect lipids and serum glucose. USE IN PRACTICE: CCBs are also a heterogenous class of drugs composed of the phenylalkylamine verapamil, the benzothiazepine diltiazem, and the large group of dihydropyridines (DHPs) with the prototype nifedipine, and an increasing number of newer agents (e. g. nitrendipine, nisoldipine, amlodipine, felodipine, lacidipine and lercanidipine). DHPs are primarily vasodilators, lowering blood pressure by decreasing peripheral vascular resistance at the level of the small arterioles which can be followed by an autonomic counterregulation especially in drugs with a rapid onset of action. This is markedly reduced or abolished in the treatment with the modern long acting DHPs and is also not the case in the treatment with non-DHPs. Prospective randomized controlled outcome studies demonstrated a significant reduction in stroke in elderly patients with isolated systolic hypertension compared with placebo (Syst-Eur [Syst-China]), and no significant differences in cardiovascular mortality and combined morbidity compared with diuretics, beta blockers or ACE-Inhibitors (STOP-2, INSIGHT, NORDIL, ALLHAT, INVEST). To normalize the blood pressure it is mostly necessary to combine antihypertensive drugs. Here are CCBs ideal partners for a therapy with ACE-inhibitors, AT1 antagonists or beta blockers (DHP) and diuretics (verapamil). With respect to the antihypertensive differential therapy the author recommends CCBs based on studies with the evidence grade 1-3; especially for elderly hypertensives (with isolated systolic neuhypertension and a high risk of stroke), for patients with COPD and asthma bronchiale, Raynaud's syndrome or Prinzmetal-angina, patients with diastolic function disturbances including diastolic heart failure or hypertensives with massive left ventricular hypertrophy (in combination with ACE or AT1 inhibitors).     

Pathophysiology of antihypertensive therapy with diuretics.

Recent progress in antihypertensive therapy has widened the selection of drugs, and large clinical trials have attracted attention to newer classes of antihypertensives. Consequently, the use of diuretics as antihypertensive agents has been relatively reduced, particularly since the newer drugs are associated with fewer adverse metabolic reactions. However, diuretics have a specific activity of removing sodium from the body fluid, thereby rendering the blood pressure insensitive to sodium intake, relieving the overload to systemic circulation, and normalizing the circadian rhythm of blood pressure from a non-dipper to a dipper pattern. At low doses, diuretics are known to be as effective as all other antihypertensive agents for reducing nearly all types of cardiovascular events. In this brief review, the indication for thiazide diuretics will be discussed based on the pathophysiology of hypertension and antihypertensive therapy with diuretics mainly from the point of view of sodium metabolism. Low-dose diuretics will continue to be an important agent in the treatment of hypertension, mostly in combination with vasodilators such as modulators of the reninangiotensin system and calcium channel blockers.     

Guidelines for management of hypertension: report of the third working party of the British Hypertension Society.

Use non-pharmacological measures in all hypertensive and borderline hypertensive people. Initiate antihypertensive drug therapy in people with sustained systolic blood pressures (BP) >/=160 mm Hg or sustained diastolic BP >/=100 mm Hg. Decide on treatment in people with sustained systolic BP between 140 and 159 mm Hg or sustained diastolic BP between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease or a 10-year coronary heart disease (CHD) risk of >/=15% according to the Joint British Societies CHD risk assessment programme/risk chart. In people with diabetes mellitus, initiate antihypertensive drug therapy if systolic BP is sustained >/=140 mm Hg or diastolic BP is sustained >/=90 mm Hg. In non-diabetic hypertensive people, optimal BP treatment targets are: systolic BP <140 mm Hg and diastolic BP <85 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is <150/<90 mm Hg. Despite best practice, these levels will be difficult to achieve in some hypertensive people. In diabetic hypertensive people, optimal BP targets are; systolic BP <140 mm Hg and diastolic BP <80 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is <140/<90 mm Hg. Despite best practice, these levels will be difficult to achieve in some people with diabetes and hypertension. In the absence of contraindications or compelling indications for other antihypertensive agents, low dose thiazide diuretics or beta-blockers are preferred as first-line therapy for the majority of hypertensive people. In the absence of compelling indications for beta-blockade, diuretics or long acting dihydropyridine calcium antagonists are preferred to beta-blockers in older subjects. Compelling indications and contraindications for all antihypertensive drug classes are specified. For most hypertensives, a combination of antihypertensive drugs will be required to achieve the recommended targets for blood pressure control. Other drugs that reduce cardiovascular risk must also be considered. These include aspirin for secondary prevention of cardiovascular disease, and primary prevention in treated hypertensive subjects over the age of 50 years who have a 10-year CHD risk >/=15% and in whom blood pressure is controlled to the audit standard. In accordance with existing British recommendations, statin therapy is recommended for hypertensive people with a total cholesterol >/=5 mmol/L and established vascular disease, or 10-year CHD risk >/=30% estimated from the Joint British Societies CHD risk chart. Glycaemic control should also be optimised in diabetic subjects. Specific advice is given on the management of hypertension in specific patient groups, ie, the elderly, ethnic subgroups, diabetes mellitus, chronic renal disease and in women (pregnancy, oral contraceptive use and hormone replacement therapy). Suggestions for the implementation and audit of these guidelines in primary care are provided.     

Drug treatment of hypertension in older persons in an academic hospital-based geriatrics practice.

OBJECTIVE: To investigate the prevalence of hypertension in older persons, the prevalence of the different antihypertensive drugs used to treat hypertension, the prevalence of the different antihypertensive drugs used to treat hypertension in persons with prior myocardial infarction (MI) or congestive heart failure (CHF), and the prevalence of lowering the blood pressure to <140/90 mm Hg with therapy. DESIGN: A retrospective analysis of charts from all older patients seen from December 1, 1997, through August 31, 1998, at an academic, hospital-based geriatrics practice was performed to investigate the prevalence of hypertension in older persons, the prevalence of different antihypertensive drugs used to treat hypertension, the prevalence of different antihypertensive drugs used to treat hypertension in persons with prior MI or CHF, and the prevalence of lowering the blood pressure to <140/90 mm Hg with therapy. SETTING: An academic hospital-based geriatrics practice staffed by fellows in a geriatrics training program and fulltime faculty geriatricians. PATIENTS: A total of 459 men and 1360 women, mean age 80 +/- 8 years (range 59 to 101 years), were included in the study. MEASUREMENTS AND MAIN RESULTS: Hypertension was present in 1051 of the 1819 persons in the study (58%). Target organ damage, clinical cardiovascular disease, or diabetes mellitus was present in 738 (70%) of these 1051 persons. Of the 1051 persons with hypertension, 520 (49%) were treated with diuretics, 297 (28%) with beta-blockers, 445 (42%) with angiotensin-converting enzyme (ACE) inhibitors, 171 (16%) with calcium channel blockers, and 13 (1%) with other antihypertensive drugs; 41 (4%) received no antihypertensive therapy. The last blood pressure recorded on the chart was <140/90 mm Hg for 735 of the 1051 persons (70%) with hypertension. Of 306 persons with hypertension and prior MI, 182 (59%) were treated with beta-blockers, 146 (48%) with ACE inhibitors, 96 (31%) with diuretics, and 29 (9%) with calcium channel blockers. Of 103 persons with hypertension and CHF, 103 (100%) were treated with diuretics, 94 (91%) with ACE inhibitors, 22 (21%) with beta-blockers, and 3 (3%) with calcium channel blockers. CONCLUSIONS: The prevalence of hypertension in the 1819 older persons seen in an academic, hospital-based geriatrics practice was 58%. Educational efforts led to increased use of diuretics and beta-blockers and decreased use of calcium channel blockers in treating hypertension. The last blood pressure recorded on the chart was <140/90 mm Hg in 70% of older persons with hypertension in the study.     

Heart Failure in ALLHAT: Did Blood Pressure Medication at Study Entry Influence Outcome?

Lower heart failure (HF) rates in individuals taking chlorthalidone vs amlodipine, lisinopril, or doxazosin were unanticipated in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). HF differences appeared early, leading to questions about the possible influence of pre‐enrollment antihypertensive drugs. A post hoc study evaluated hospitalized HF events. During year 1479 individuals had HF, with pre‐entry antihypertensive medication data obtained on 301 patients (63%). Case‐only analysis examined interactive effects (interaction odds ratio [OR, ratio of ORs]) of previous medication and ALLHAT treatment on HF outcomes, eg, did treatment effect differ by pre‐entry antihypertensive class? Among cases, 39%, 37%, 17%, and 47% were taking pre‐entry diuretics, angiotensin‐converting enzyme inhibitors, β‐blockers, and calcium channel blockers, respectively. Interaction OR for year 1 HF for amlodipine vs chlorthalidone for patients taking vs not taking diuretics pre‐entry was 1.08 (95% confidence interval [CI], 0.53–2.21; P=.83); for lisinopril vs chlorthalidone, 1.33 (95% CI, 0.65–2.74; P=.44); and for doxazosin vs chlorthalidone, 1.13 (95% CI, 0.57–2.25; P=.73). Controlling for other pre‐entry antihypertensives yielded similar results. There was no significant evidence that pre‐entry drug type explained observed hospitalized HF differences by ALLHAT treatment.     

Blood Pressure Control by Drug Group in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

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=9048), or lisinopril 10–40 mg/d (n=9054) in a randomized double‐blind hypertension trial. Participants were hypertensives aged 55 or older 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 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (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. BP control was achieved in the majority of each randomized group—a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.     

The place of diuretics in preventing cardiovascular events

Low-dose diuretics are recommended for the initial choice of antihypertensive therapy in the 7th US Joint National Committee report and are accepted as an appropriate choice among other classes of drugs in the 2003 European Society of Hypertension guidelines. The rationales for the use of low-dose diuretics include the following: Renal dysfunction interfering with normal natriuresis is likely a fundamental defect in the pathogenesis of hypertension. Subtle renal insufficiency that interferes with sodium excretion is a common consequence of uncontrolled hypertension. Diuretic-based therapy has been clearly documented in placebo-controlled, randomized trials to reduce cardiovascular morbidity and mortality, particularly in the treatment of elderly hypertensives.In multiple comparative trials, diuretic-based therapy has been shown to provide equal cardiovascular protection to that provided by newer agents. Diuretics enhance the antihypertensive efficacy of all other classes of agents. As lower blood pressure goals of therapy have been found to be needed, diuretic enhancement of other agents' efficacy has become even more essential. With such low doses, side effects are minimal in degree and infrequent in appearance.     

Resistant hypertension: comparing hemodynamic management to specialist care

Although resistant hypertension affects a minority of all hypertensives, this group continues to experience disproportionately high cardiovascular event rates despite newer antihypertensive agents. Hypertension represents an imbalance of hemodynamic forces within the circulation, usually characterized by elevated systemic vascular resistance. We studied the utility of serial hemodynamic parameters in the selection and titration of antihypertensive medication in resistant hypertensive patients using highly reproducible noninvasive measurements by thoracic bioimpedance. Resistant hypertension patients (n=104) were randomized to drug selection based either on serial hemodynamic (HD) measurements and a predefined algorithm or on drug selection directed by a hypertension specialist (SC) in a 3-month intensive treatment program. Blood pressure was lowered by intensified drug therapy in both treatment groups (169+/-3/87+/-2 to 139+/-2/72+/-1 mm Hg HD versus 173+/-3/91+/-2 to 147+/-2/79+/-1 mm Hg SC, P<0.01 for systolic and diastolic BP), using similar numbers and intensity of antihypertensive medications. Blood pressures were reduced further for those treated according to hemodynamic measurements, resulting in improved control rates (56% HD versus 33% SC controlled to 相似文献   

Does ALLHAT change the management of hypertension in chronic kidney disease?

ALLHAT was designed to test the hypothesis that “newer” antihypertensive agents are superior to a thiazide diuretic for cardiovascular outcomes. Pre-specified secondary outcomes included the development of endstage renal disease (ESRD) (dialysis, renal transplantation, or death from renal cause) and estimated glomerular filtration rate (GFR). ALLHAT showed no differences in the overall rates of ESRD between those randomized to chlorthalidone, amlodipine, or lisinopril. It showed a slower rate of decline of GFR among those randomized to amlodipine in both diabetics and nondiabetics, and in the composite end point (ESRD or ≥ 50% decline in GFR) in nondiabetics. The results of ALLHAT are consistent with other studies that, for the patient population studied (presumably largely nonalbuminuric patients with and without diabetes), at systolic BP < 130 mm Hg, there is no difference for renal outcomes between a thiazide diuretic, dihydropyridine calcium channel blocker, and ACEI-initiated treatment for 5 to 6 years of follow-up. These results suggest that BP control per se remains the most important objective for this patient population.