Relevance of the plasma renin hormonal control system that regulates blood pressure and sodium balance for correctly treating hypertension and for evaluating ALLHAT

T he primary findings of the Anti-hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were published on December 18, 2002, in the Journal of the American Medical Association.1 ALLHAT is the largest trial of its kind, involving the 5-year participation of 33,357 hypertensive patients in North America. The trial was funded by the National Heart Lung and Blood Institute (NHLBI) at a cost of more than 120 million dollars, not including a 40 million dollar grant to NHLBI from Pfizer whose two drugs, the !-blocker doxazosin, and the calcium-channel blocker (CCB) amlodipine served as two of the four primary comparator drug types, along with lisinopril and chlorthalidone (hygroton). In addition to a large steering committee of some 57 healthcare professionals, hundreds of other physicians and professionals participated in ALLHAT on an almost daily basis. The ALLHAT patients had a mean age of 67 years, 36% had diabetes, and 35% were African Americans. At the outset of the trial less than 30% of the patients had their seated blood pressures (BPs) controlled to the ALLHAT goal of !140/90 mm Hg. The ALLHAT study design has some unique features: first 90% of their patients were already receiving antihypertensive drug treatments and on day 1 of the study were simply switched to one of the four primary blinded randomized drug limbs (hygroton, doxazosin, amlodipine, or lisinopril). Thus, “baseline” BP was not a meaningful control point to evaluate the absolute depressor effectiveness of the trial drugs. Second, the doxazosin limb had to be stopped because of the appearance of “heart failure,” characterized by ill-defined edema. This problem was perhaps related to the abrupt switch of prior diuretic or other types of antihypertensive drugs to the weaker doxazosin. But, this occurrence of congestive heart failure (CHF) was anomalously, much greater than in other trials, and not followed by the usual increases in CHF mortality. Accordingly, we probably can dismiss the heart failure increment of the first year as too atypical. Third, as I discuss later, the lisinopril limb was denied the use of a diuretic or other natriuretic V drug as a step 2 drug and obliged to superimpose other anti-R drugs, atenolol, reserpine, or clonidine. Despite this disadvantage, with its resulting higher mean BP, the lisinopril limb was still just as good as the hygroton or amlodipine limbs for protecting from the two primary cardiac end points of the study and almost as good for protecting from stroke or heart failure. In this setting, the ALLHAT study groups, including their investigators, officers, and coordinators concluded that their data demonstrate that patients receiving the older and cheaper drug, chlorthalidone, actually had fewer strokes and less heart failure than did the rest and therefore, even if the statistics were weak and the two situations were extenuating, chlorthalidone was declared “superior” or “unsurpassed” by all other drugs for treating all hypertension, first and always, and also for preventing or treating later heart failure or stroke. To treat hypertension the investigators found that two or three drugs were needed in more than 60% of their patients to achieve goal BP in 67% by using their hygroton first strategy. These broad conclusions were drawn despite the fact that the predetermined primary end points that the study was powered to examine, ie, the occurrence of fatal coronary disease or nonfatal myocardial infarction MI, showed absolutely no significant differences between the three drug treatment limbs that started with hygroton, amlodipine, or lisinopril.