it was established by the 1980 's that drug treatment of elevated blood pressure ( bp ) reduces the risks of cardiovascular complications of hypertension .
the prevailing assumption among clinicians and regulators was , and probably continues to be , that the benefits of antihypertensive treatment were a direct consequence of the reduction in systolic and/or diastolic bp .
based on this premise , we have seen a flood of new antihypertensive agents from multiple classes of drugs introduced into the marketplace .
the scientific documentation has often consisted of small , short - term trials . as long as the new agents are superior to placebo in reducing bp , and as long as they are reasonably free of side effects , the drugs receive regulatory approval .
clinicians now have more than 100 antihypertensive drugs from which to choose . because the blood - pressure - lowering potential of these drugs is fairly similar , use of individual pharmaceutical agents is determined more by marketing forces than by science .
a health services concern is that there is a greater than 20-fold difference in drug cost .
the key question today is , " does it matter how elevated bp is lowered ? "
this question is best answered by randomized clinical trials that compare antihypertensive agents . however , a number of issues and concerns have been raised about the design of these trials .
regulatory agencies prefer placebo - controlled trials , since they want to know whether a drug is effective for its intended use and whether it is reasonably safe .
comparative or active - controlled trials have other objectives and provide answers along the superiority  inferiority axis .
although extremely relevant clinically , the regulatory agencies have limited interest and use for information regarding which drug is superior .
comparative trials are a cause for concern to the pharmaceutical industry , since such trials may produce losers ( inferior drugs ) , whereas the outcome of placebo - controlled trials of new antihypertensive agents is , for the industry , less risky . to lessen the risks that a drug may be inferior to that of a competitor
, there is an unfortunate tendency to compare the new agent to the least effective standard therapy , sometimes in an inadequate dose .
another approach is to proceed with only a small sample size , which is inadequate to detect reliably meaningful differences among drugs .
the antihypertensive and lipid - lowering treatment to prevent heart attack trial ( allhat ) , initiated in 1994 , was one of the first major comparative trials with clinical outcomes .
its strengths include : independent sponsorship ( the national heart , lung , and blood institute ) ; its scope ( comparison of 4 drugs from different drug classes ) ; optimal selection of standard / control treatment ( low - dose diuretics ) ; a double blind design ; its sample size ( 40,000 high - risk hypertensives to be treated for 48 years ) ; and the selection of trial outcomes ( all major vascular complications of hypertension ) .
allhat addresses the question of whether representatives of the newer and more expensive antihypertensive agents : lisinopril ( angiotensin - converting enzyme inhibitor ) , doxazosin ( alpha - blocker ) , and amlodipine ( calcium - channel blocker ) , are more effective as first - line drugs than a generic agent , chlorthalidone ( low - dose diuretic ) , in reducing the risk of cardiovascular disease .
first , there was a highly significant ( 25% ) excess risk of major cardiovascular events ( a prespecified secondary endpoint ) in the doxazosin group in comparison to the chlorthalidone group .
second , the likelihood of doxazosin emerging as superior to low - dose chlorthalidone was very remote .
this excess of cardiovascular events with doxazosin was driven by a doubling in the risk of congestive heart failure , both primarily hospitalized and fatal cases .
the annual heart failure rate was 2% in the doxazosin group but 1% in the chlorthalidone group .
in addition , there was a 20% excess in the relative risk of stroke , and 15% excesses in coronary revascularizations and angina , in the doxazosin group .
however , the risks of major coronary events ( the prespecified primary endpoint ) and all - cause mortality were not different between the two treatment groups .
the fact that the achieved blood pressures were similar throughout the duration of the trial indicates that non - blood - pressure - related mechanisms are involved , which could explain these differences .
the more persuasive ones conclude that alpha - blockers should no longer be considered first - line agents for hypertension in high - risk , elderly adults [ 4 - 6 ] . others raise questions of a technical nature , but fail to realize the public health implication of the allhat findings [ 7 - 9 ] . among the approximately one million users of doxazosin in the united states and europe
, one could expect as many as 10,000 unnecessary cases of advanced heart failure every year .
krakoff   raises a critical question , " should the results of allhat be considered as revealing drug toxicity or of the lesser charge of ineffectiveness ? "
he suggests that doxazosin , " may be ineffective and perhaps little better than placebo , for the many patients at higher risk for heart failure " .
regardless of the answer , actions should be taken to inform treating clinicians . to date , the manufacturer of doxazosin , pfizer , has refused to issue even a " dear doctor " letter with a proper warning . the other two commentaries by gavras and gavras   and hooper   discuss potential mechanisms behind the observed excess of cardiovascular events .
gavras and gavras speculate that alpha - adrenergic blockage would lead to small elevations of arginine vasopressin .
this systemic pressor hormone could become important through its pressor action in elderly patients and in those with diabetes , triggering congestive heart failure and myocardial ischemia .
these proteins have vital functions in the body , protecting cells from injury through multiple mechanisms .
alpha - adrenergic stimulation with norepinephrine increases the levels of heat shock proteins , while alpha - adrenergic blockade decreases it .
a drug - induced decrease could lead to increased vulnerability of the cardiovascular system to injury .
. we may never know with certainty why doxazosin had unfavorable cardiovascular effects in allhat .
however , we stand on a solid scientific foundation when we conclude that doxazosin is an inferior antihypertensive agent and it should only be used if first - line agents  low - dose diuretics , beta - blockers , and angiotensin - converting enzyme inhibitors  fail to achieve blood pressure control or can not be tolerated .
 the key question in hypertension research today is , " does it matter how elevated blood pressure is lowered ? " 
 the antihypertensive and lipid - lowering treatment to prevent heart attack trial ( allhat ) initiated in 1994 serves as a model for comparative trials . 
 its strengths include its independent sponsorship , scope and design . 
 the alpha - blocker arm was stopped early ; doxazosin was shown to be clearly inferior to low - dose chlorthalidone not only in preventing heart failure , but also stroke , in spite of similar blood pressure reduction . 
 the findings have major public health implications as pointed out by krakoff in this journal . 
 other commentaries by gavras and gavras and hooper discuss possible mechanisms behind the excess of cardiovascular events in doxazosin - treated patients . 
None
Competing interests
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