Linda Brookes, MSc
Three New York researchers, including John H Laragh, MD (New York Hospital/Cornell University Medical Center, New York, NY), founder of the American Society of Hypertension (ASH), recently challenged the findings of ALLHAT (the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) in the American Journal of Hypertension.[1-3] Subsequently, at a press briefing held in New York City during the 18th Annual Scientific Meeting of ASH, they extended their criticisms to the recently released Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).[4,5] They believe that JNC 7 has been inappropriately based on the ALLHAT results. Dr. Laragh, along with Lawrence M Resnick, MD (Weill College of Medicine, New York, NY) and Jay Meltzer, MD (Columbia University of Physicians and Surgeons, New York, NY) all expressed their opposition to the way the JNC guidelines have been produced and spoke out about what they see as intimidation toward any criticism of the government-produced JNC 7 report.

The "Two Basic Types" Theory of Hypertension Was Ignored

30%-35%的高血压患者病因是盐，另50%-60%患者病因是高血浆肾素，所以在去盐（利尿剂）无法奏效时就要降肾素（ACEI和ARBs），最合适的才是最好的。
"从根本上解决问题"是最理想的，但首先应该知道的是"根本"是什么？在确切原因还能不完全明了时，只能基于现有的知识，有重点的、综合的分析解决，无论用哪种方式？选择哪种药？用药的目的是治病，能治好病就是首选。

Dr. Laragh is highly critical of the overall development of the JNC guidelines. Over the past 25 years during which JNC reports have been produced, science has leaped forward but JNC has leaped nowhere, he declared, adding that the latest recommendations are little different from the first JNC report,[6] published in 1977 after it was discovered that blood pressure could be lowered with diuretic-based therapy. Since that time, JNC has repeatedly recommended the use of diuretics. In JNC 5, ACE inhibitors and beta-blockers were added as first-line therapy, but although the recommendations were based on evidence from clinical trials, these 2 classes of agents were removed in JNC 6 and JNC 7, respectively, he noted.

Dr. Laragh proposes that 2 causes of hypertension be recognized: salt and increased plasma renin. According to Laragh, salt accounts for 30% to 35% of the incidence of hypertension, so many patients only need a desalting drug such as chlorthalidone or hydrochlorothiazide (HCTZ), or spironolactone, which Dr. Laragh prefers as a safer alternative and which is also off patent and therefore inexpensive. The other 50% to 60% of people with high blood pressure have hypertension caused by high plasma renin (plasma renin activity [PRA] > 0.65 ng/mL/h).
According to Dr. Laragh, the only reason to treat high blood pressure is not to correct the blood pressure levels per se, but rather to avoid the future occurrence of MI, stroke, renal failure, or heart failure, and the only drugs that are known to protect against these are the anti-renin system drugs, ie, ACE inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers. All of these agents lower or block renin and all give measurable and immediate protection from MI, stroke, heart and kidney failure. Dr. Laragh takes issue with the fact that although the literature on this is extensive, none of it was mentioned in the ALLHAT or the JNC 7 reports.

As a result of this simple dichotomous analysis of hypertension, patients in whom diuretics like chlorthalidone, HCTZ, or spironolactone are not effective should be switched to an antirenin drug. Renin testing, which is now widely available, can be used to more quickly identify whether a patient has salt (low-renin) hypertension or high-renin hypertension. Thus, two thirds of all hypertension can be corrected with monotherapy, according to Dr. Laragh. This can be done because it involves using a drug mechanistically, which it is only possible to do with the correct drug. However, there can be no such certainty when patients are given 3 drugs. Dr. Laragh noted that in ALLHAT, the diuretic was continued indefinitely throughout the duration of the trial, with other drugs added on. Thus the negative effects of the diuretic canceled out the value of the antirenin drug. Around 63% of patients in ALLHAT took 3 drugs to control their blood pressure, whereas, according to Dr. Laragh, 65% of his patients are controlled with 1 drug.

In support of his theory and practice, Dr. Laragh cites ANBP2 (the Second Australian National Blood Pressure Study),[7] which compared treatment with a desalting drug, hydrochlorothiazide (HCTZ), to treatment with an antirenin agent, enalapril. Patients who did not respond to the first drug were switched to the other. After 5 years, the ACE inhibitor was found to be superior to a diuretic for correcting hypertension, and monotherapy in two thirds of patients was not only found to be possible but superior. This result was achieved because each patient received the right drug, thus confirming his theory, Dr. Laragh concludes.

ALLHAT and JNC 7 Express -- Unbelievably Fast?

试验结论的得出是基于主要终点，还是次要终点？怎样选择试验对象？什么样的临床试验才具有其价值？ 科学客观、设计合理、执行严格、组织严密，才是有科学价值的临床试验。

In his critique, Dr. Melzer questioned why both the ALLHAT and JNC 7 reports appeared as " JAMA express," for which the peer-review process time is 24-48 hours and the time for authors' response is 72 hours. In the case of ALLHAT, Dr. Meltzer doubts that the report could have been reviewed within this period of time or that all the many authors could have responded within 72 hours. In the case of JNC 7, he questions the need for an express version of a report that essentially made only 2 changes since JNC 6: the creation of the category "prehypertension" and the recommendation, based on ALLHAT, that most patients should be started on a diuretic.

Dr. Meltzer also criticized the ALLHAT report for basing its conclusion on a secondary endpoint when the trial was originally intended to make recommendations only on the basis of the results of its primary endpoints. Secondary endpoints constitute useful data, but are collected mainly for hypothesis generation and the elucidation of possibilities for further studies, Dr. Meltzer pointed out. Another change in ALLHAT since its rationale and design was published[8] was its appearance as a study of first-step therapy. However, ALLHAT could not be a first-step study because 90% of patients were already on antihypertensive medications for an unknown number of years before they were entered into the trial. In contradistinction to most other studies of this nature, there was no washout period in ALLHAT, Dr. Meltzer noted. Initial blood pressure was never recorded, so there was no baseline on which to judge first-step response, he declared. To call ALLHAT a study of first-step response is post hoc reasoning, he believes.

Prehypertension: Creating More Patients "by Fear"

Dr. Laragh referred to the new JNC 7 category of prehypertension as "creating 45 million more patients by fear." No one knows whether "prehypertension" really exists. It does not define anything; it only guesses at what might happen, he stated. His colleague, Dr. Resnick, said that the idea of calling people with blood pressure of 120/80 mm Hg prehypertensive is "the biggest garbage I have ever heard in my life." He stated that in the early years of treating hypertension, the aim was to treat the people who need to be treated and to leave the others alone, not make their lives more difficult. That focus has been lost now, because everyone in a population is regarded as the same. Instead of this general approach, however, the approach should be tailored for individual people, according to Dr. Resnick, and he hopes that most doctors will not take this new category seriously and that the population will not be worried about "this stuff."

Dr. Meltzer pointed out that there is nothing new about prehypertension, since it was previously called high normal. It was associated with an increased cardiovascular risk, but the degree of risk is very small and patients are not always willing to change their lives in order to improve a statistic that may be far in the future.

Dr. Laragh strongly believes that the lifestyle changes recommended for prehypertensive individuals will not work because they are too difficult for people to follow. Dr. Resnick agreed, saying that they will only work in a formal program.

Individual Therapy for Individual Patients

Dr. Resnick believes that physicians are being told to practice as if every patient were the same, whereas the underlying principle of practice over the past 30 years has been to find out about each individual patient and decide what the best drug or advice is for that patient. Large numbers of patients are not needed to demonstrate an effect; in fact, the larger the clinical trial, the more irrelevant it is for the doctor treating patients, Resnick believes. Such trials are not a good basis for guidelines as to what is the best drug for patients. The best a physician can do is to look at the individual. It is easy to see whether patients are young or old, black or white, etc, and to do tests such as renin measurement to find out something that allows the physician to judge what is best for that patient. This is the normal medical approach and in the long term it will be cheaper; the patient will be on fewer medicines and on lower doses, Dr. Resnick believes.

Conflict of Interest
The JNC guidelines were originally suggestive and now they are becoming coercive, Dr. Laragh believes. He sees a major conflict of interest in the governmental operation. He claims that physicians are not free to criticize the National Institutes of Health. "I no longer need huge government grants, so I can tell them to go to hell," he joked, but stressed that other researchers may risk their livelihood in doing so.