Commentary for Debate - the ALLHAT-Study

Endocrinologists and diabetologists are increasingly confronted with the tidal waves induced by one of largest trials ever performed in hypertension treatment - the ALLHAT study ([ALLHAT, 2002]). This disease has so many endocrinological aspects and strong ties with diabetes that yet another commentary seems necessary in ECED.

Even a mega-trial like ALLHAT can miss the reflection of reality. The main reason for this is its terrible age which - from the first planning to its completion - is around 12 years. Despite the “maturity” of the data there are several shortcomings which should oblige to exercise caution in the interpretation of the results:

A primary treatment arm with β-blockers is lacking. What is particularly appalling is the fact that despite the prevalence of coronary heart disease and/or diabetes in nearly half the patients, β-blockers were not given in the first line. This is highly unethical as there is a clear differential indication for β-blockers in ischemic heart disease and maybe even diabetes. I do not want to anticipate how a modern IRB (ethics committee) would decide if asked for ethical judgement on the study. Diuretics as first line treatment of hypertension have been accepted for more than two decades. However, their main disadvantage clearly is the high prevalence of non-compliance or the observation of a low persistence in clinical reality (Caro et al., 1999). This is even complicated by the necessity to frequently control electrolytes for the prevention of side effects. A clinical trial, even of such tremendous size as the ALLHAT-study, clearly does not reflect daily life conditions. Promoting a treatment (Appel, 2002) which in reality is not existent at all in a large portion of patients is a bad advice to the medical community and especially to the patients. In ALLHAT almost half of the patients needed combination treatment. Atenolol, clonidine or reserpine were combination partners. It has to be stated that due to the age of the study latter two compounds appear rather obsolete today in the treatment of uncomplicated arterial hypertension. Thus most of the data of the ALLHAT-study is as obsolete as the drugs used. The past ten years have taught us valuable lessons about differential therapy of hypertension with modern drugs such as angiotensin-antagonists or have even revitalized β-blockers because of their life prolonging actions in one of the most prevalent complications of hypertension, namely heart failure. No such developments in rapidly progressing fields of science can be reflected by a 12 year old study. The conclusion which might be drawn from ALLHAT that blood pressure has to be lowered by anything which is cheap turns the clock back by at least ten years. Propagation of diuretics leads to non-therapy in a practical setting which is the worst possible treatment. ALLHAT is only valid for conclusions regarding the first line treatment in form of a monotherapy. As treatment goals of arterial hypertension are being lowered every year, monotherapy applies to a vanishing portion of hypertensive patients. For a treatment goal of 130/85 mm Hg monotherapy may only be sufficient for one fourth of the patients. Therefore ALLHAT deals with a question which applies only to a minority of patients. If one constructs an order of requirements which have to be met by modern antihypertensive therapy, ALLHAT should rather be read like this: Antihypertensive therapy is better than no therapy The choice of drugs has to take into account both concomitant diseases and compliance The cost of treatment should be secondary to b), because otherwise a) applies as no therapy is the result ALLHAT promotes an antihypertensive drug - a thiazide diuretic - which has been known for many years to induce or advance the metabolic syndrome and diabetes mellitus as shown for another time in ALLHAT (ALLHAT, 2002) ALLHAT is an important study; unfortunately, however, it describes a dinosaur and largely ignores newly developed, versatile and successful mammals. ALLHAT reflects the unsolvable problems of mega-trials lasting longer than ten years: By no means they are able to reflect the revolutionary pace of scientific progress in medicine. Therefore, strictly evidence based medicine in antihypertensive therapy needs to be combined with thoughtful projections on the base of smaller and more recent trials. Otherwise treatment of patients will be outdated and progress nullified.

References

• 1 Appel L J. The verdict from ALLHAT-thiazide diuretics are the preferred initial therapy of hypertension.  JAMA. 2002;  288 3039-3042
• 2 Caro J J, Speckman J L, Salas M, Raggio G, Jackson J D. Effect of initial drug choice on persistence with antihypertensive therapy: The importance of actual practice data.  CMAJ. 1999;  160 41-46
• 3 The ALLHAT officers and coordinators for the ALLHAT collaborative research group . Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).  JAMA. 2002;  288 2981-2997