March 2001
Stephen Marer, MD
Torence Memorial Hospital
Los Angelas, CA
HIGHLIGHTS
- ALLHAT is comparing the efficacy of other antihypertensive classes in reducing CVD risk to diuretics
- The alpha-blocker (doxazosin) arm of ALLHAT was discontinued early
- There was a two-fold increase in CHF with doxazosin when compared to chlorthalidone, and smaller increases in stroke, and combined CVD
- There was no difference in fatal endpoints of CHD and non-fatal MI between doxazosin and chlorthalidone
- Alpha-blockers should not be used as first-line agents in hypertension, but are acceptable as second-line agents
- ALLHAT should yield data by 2002-2003 on ACE inhibitors, Calcium channel antagonists, and lipid-lowering therapy
|
Approximately 50 million Americans have hypertension, and tens of millions more will develop the condition as they age. More importantly, hypertension is directly related to coronary heart disease (CHD) and stroke, the first and third leading causes of death, respectively, in this country. Previously steep declines in the rates of CHD and stroke have begun to level off or even slightly increase in recent years, underscoring the need for appropriate treatment of hypertension as a matter of public health. Practitioners and patients alike need to know that the main goal in treating hypertension is to reduce morbidity and mortality, primarily from CHD, stroke, congestive heart failure (CHF), and other manifestations of cardiovascular disease (CVD). Different antihypertensive therapies might not all reduce the risk of CVD equally.
Efficacy of Different Classes of Antihypertensive Medications
The different classes of antihypertensive medications have roughly equivalent efficacy in decreasing systolic and diastolic blood pressure. Whether all classes of antihypertensive medications equally decrease the risk of CVD, however, is a question without a firm answer. Over the last few decades, a convincing evidence base of large randomized trials has developed demonstrating that diuretics (thiazides or derivatives) and beta blockers do significantly reduce the risk of stroke, CHF, and CHD (Figure 1). Data on the ability of other classes of antihypertensive medications to reduce cardiovascular complications is either not as well established or lacking entirely.
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), in its last two reports, JNCV and JNCVI, departed from its earlier position by recommending diuretics and/or beta-blockers as first-line therapy for uncomplicated hypertension. It should be noted that JNC VI recommends the use of agents other than diuretics and beta blockers in patients with certain “compelling indications” where good data suggest a clinical benefit (for example: ACE-inhibitors in patients with diabetes and proteinuria). JNC VI also recommends that there are “special indications” for the use of alpha blockers to simultaneously treat dyslipidemia or prostatism and hypertension. Despite the JNC VI recommendations, the use of diuretics and beta blockers is declining in the United States as the use of newer agents, particularly ACE inhibitors and calcium channel antagonists, is increasing (Figure 2).
The disparity between prescribing practices and the JNC recommendations emphasizes the need for large randomized clinical trials that will help determine whether all classes of antihypertensive medications are equivalent in reducing CVD. Such trials may also answer the question of whether some classes of antihypertensive drugs are more effective than diuretics and beta blockers in reducing CVD. This possibility is especially pertinent to CHD because in large clinical trials diuretics and beta blockers have not always succeeded in reducing CHD events to the extent that one might predict from observational studies (particularly in younger hypertensives). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is one of the first large ongoing trials that will assess the ability of antihypertensive therapy other than diuretics and beta blockers to decrease cardiovascular morbidity and mortality. ALLHAT has already revealed important information about one class of antihypertensive medication, the alpha-adrenergic receptor blockers.
Alpha Adrenergic Receptor Blockers
Selective alpha blockers (including doxazosin, prazosin, and terazosin) act by blocking the catecholamine-mediated activation of post-synaptic alpha-1 receptors. A number of effects follow from this blockade. Venous and arterial vessels dilate, thereby lowering peripheral resistance, preload, and blood pressure, without a significant change in cardiac output. The selectivity (for alpha-1 receptors) of these agents blunts the reflex sympathetic stimulation and increase in renin and aldosterone levels seen with non-selective alpha-blockers (eg, phentolamine). Additionally, alpha-blockers relax prostatic smooth muscle and are widely used to ameliorate the symptoms of benign prostatic hypertrophy (BPH).
Alpha-blockers have theoretical advantages over some of the other classes of antihypertensive medications. They are as potent as other classes of antihypertensive medications at lowering blood pressure (Figure 3). They do not cause metabolic disturbances, such as hypokalemia and hypomagnesemia. They tend to have favorable effects on lipids, specifically decreasing LDL-cholesterol and increasing HDL-cholesterol. They can improve glucose tolerance and reduce insulin resistance. Finally, as discussed above, their selectivity is felt to be beneficial in blunting reflex sympathetic stimulation and increase in renin and aldosterone levels. Prior to ALLHAT, many felt that alpha-blockers would prove at least as effective as diuretics and beta blockers in reducing cardiovascular events.
On the other hand, the alteration of neurohormonal homeostasis by alpha-blockers is complex and not fully understood. In contrast to their potential benefits described above, alpha-blockers can cause volume expansion, may not be fully effective in eliminating reflex sympathetic stimulation and may cause some increase in renin and aldosterone levels. As with every other class of antihypertensive medication, alpha-blockers, whatever their theoretical benefits, require the endorsement of large clinical trials before their use as first-line agents in hypertension can strongly be advocated.
The ALLHAT Trial
Launched in 1994, ALLHAT is a randomized, double-blind, active-controlled trial involving more than 40, 000 patients. Its objective is to compare the benefit of a well-studied diuretic, chlorthalidone (active-control), with that of three other classes of antihypertensive medications in reducing cardiovascular events in hypertensive patients at high risk for CVD. The three other classes of antihypertensive therapy are alpha-blockers (doxazosin), ACE inhibitors (lisinopril), and calcium channel antagonists (amlodipine). ALLHAT also includes a randomized, open-label trial examining the effect of HMG-CoA reductase (pravastatin) therapy on all-cause mortality.
Hypertensive patients from the United States, Canada, Puerto Rico, and the US Virgin Islands were randomized from 1994-1998 to one of the three study arms or to the active-control arm (chlorthalidone). Requirements for inclusion in the trial were hypertension, age greater than 55 years, and at least one other risk factor (in addition to hypertension) for CHD (including prior stroke or myocardial infarction (MI), LVH, type 2 diabetes, current smoking, and a low HDL-C level). The treatment goal in the three study arms and the active-control arm is to decrease the systolic blood pressure (SBP) to less than 140 and the diastolic blood pressure (DBP) to less than 90, using the lowest possible dose of antihypertensive. In cases where the study or active-control drug cannot achieve the blood pressure goal, patients can be given, in an open-label fashion, a second or even third agent (defined as step 2 and step 3 agents respectively). Step 2 agents in ALLHAT are atenolol, reserpine, and clonidine. Hydralazine is the lone step 3 agent. The original study design called for patients to be followed until 2002. Interim results are monitored intermittently by a safety monitoring board to ensure that it is ethical to continue all arms of the trial.
The primary outcome measures in ALLHAT are fatal CHD or nonfatal MI. Secondary outcomes are all-cause mortality, stroke, combined CHD (CHD death, nonfatal MI, revascularization procedures, and hospitalized angina), and combined cardiovascular disease (CHD death, nonfatal MI, stroke, angina, coronary revascularization, CHF, and peripheral arterial disease).
Discontinuation of the Doxazosin Arm of ALLHAT
In January 2000, the ALLHAT Data and Safety Monitoring Board (DSMB) recommended early termination of the doxazosin arm of the trial. Based on this recommendation, the director of the National Heart, Lung, and Blood Institute (NHLBI) discontinued the doxazosin arm, approximately 2 years early. The results of the doxazosin data were published in April of 2000. The ACE inhibitor and calcium antagonist arms of the trial continue, as does the pravastatin part.
Between the chlorthalidone and doxazosin groups, ALLHAT had a sample size of 24,335 patients. Baseline characteristics between the two groups were similar. Data from ALLHAT showed no difference between the doxazosin group and the chlorthalidone group for the primary endpoints of fatal CHD and non-fatal MI (Figure 4). All-cause mortality, one of the secondary endpoints, was not significantly different between the two groups. The primary reason for terminating the doxazosin arm of ALLHAT was the finding of increased risk in the doxazosin group for the secondary endpoints of combined CHD, stroke and combined CVD. Most significant was a doubling of the risk for CHF in the doxazosin arm. The 4-year cumulative incidence of CHF was 8.1% in the doxazosin group compared to 4.5% in the chlorthalidone group (Figure 5). ALLHAT investigators also calculated that if the doxazosin arm were to continue until the end of the trial, there would be only a 1% chance of detecting a significant benefit of doxazosin.
One notable difference between the doxazosin and chlorthalidone arms was the mean blood pressure throughout the trial. Mean SBP was about 2-3 mm Hg higher in the doxazosin group. Based on calculations from other trials that correlates CHF incidence with changes in SBP, the ALLHAT authors concluded that an increase in the SBP by 2-3 could be expected to account for a 10-20% increase in CHF, but not twice the risk. According to the authors, however, similar calculations could explain the increased risk of stroke and angina observed in ALLHAT. As such, an increase in the incidence of CHF seems to be the primary problem arising from ALLHAT’s doxazosin arm.
Alpha-blockers and CHF
The ALLHAT data indicates that CHF was significantly more likely in the group treated with doxazosin than those treated with diuretics. However, whether doxazosin actually caused CHF, did nothing to decrease its incidence, or actually decreased the incidence (to a lesser degree than chlorthalidone) is unknown, because no placebo was used.
Why the use of doxazosin seems to be associated with an increased risk of CHF is unclear. Possible explanations for the increased incidence of CHF seen in the doxazosin group are an increase in plasma volume, elevated norepinephrine levels, overall increase in sympathetic tone, and unfavorable effects on the renin-angiotensin-aldosterone axis. In recent years, trials showing a clear benefit of beta blockers and ACE inhibitors in CHF have implicated the sympathetic nervous system and the renin-angiotensin-aldosterone axis as major factors in the pathogenesis of CHF. Given the ALLHAT findings, it is interesting to note that the one of the first beta blockers shown to be beneficial in CHF was Carvedilol, which also has some alpha blocking properties.
Implications for Clinical Practice
The main reason to treat hypertension is to decrease cardiovascular morbidity and mortality. There is no question that diuretics and beta blockers can decrease the incidence of cardiovascular events, but practitioners should remember that evidence is not as strong supporting the use of other agents in uncomplicated hypertension. Before starting a patient on first-line therapy for hypertension, there should be some probability that the therapy will be at least as effective as diuretics and beta blockers in reducing cardiovascular morbidity and mortality.
In previous trials, alpha-blockers decreased blood pressure as well as other classes of antihypertensive medications. They also boast theoretical advantages in carbohydrate and lipid metabolism over diuretics and beta blockers. However, while the data from ALLHAT does not show that doxazosin actually caused harm, the study failed to show any evidence that doxazosin was superior to diuretics in reducing cardiovascular morbidity and mortality. Moreover, ALLHAT has now raised the specter of a markedly increased incidence (compared to diuretics) of CHF when using alpha-blockers as first-line therapy for hypertension. With no other data arguing to the contrary, the proper conclusion is that alpha-blockers should not be used as first-line agents in hypertension, even in patients with BPH or dyslipidemia. It should be noted that nothing in ALLHAT disqualifies alpha-blockers as “add-on” or second-line agents. Undoubtedly, alpha-blockers will be studied as part of combination therapies, and it is possible that their metabolic and lipid effects will prove beneficial when combined with other agents.
The hypertension community eagerly awaits the presentation of the final ALLHAT data pertaining to the calcium channel blocker and ace-inhibitor arms. Such data should be available in late 2002 or 2003.
Selected References
- Kaplan, N. Clinical Hypertension. Williams and Wilkins, 1994.
- Davis BR, Cutler JA, Gordon D, et al, for the ALLHAT Research Group. Rationale and design of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). American Journal of Hypertension. 1996;9:342-360.
- The ALLHAT Research Group. Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone. JAMA. 2000;283
- The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Published by the National Heart, Lung, and Blood Institute. 1997.
- Psaty BM, Smith NL, Siscovick DS et al, Health Outcomes Associated with Antihypertensive Therapies Used as First-Line Agents. JAMA 1997;277:739-745.
- Neaton JD, Grimm RH, Prineas RJ et al, Treatment of Mild Hypertension Study (TOMHS). JAMA. 1993;270
- Siegel D, Trends in Antihypertensive Drug Use in the United States: Do the JNC V Recommendations Affect Prescribing? JAMA. 1997;278: 1745-8.
|
