Hypertension: A Turning Point in the History of Medicine...and Mankind. (Editorial).

The availability of effective and safe medication to reduce blood pressure has dramatically changed the impact and natural course of hypertension, enormously expanded the scope and influence of medicine, transformed the role of physicians in society, and may have been a turning point in the history of mankind. Before these medications were available, patients went to see their doctors only if they were not feeling well or were sick. Once these medications became available, asymptomatic and otherwise healthy people went to see their doctors to find out if they were healthy.

Doctors were now needed to reassure people that they were healthy, because feeling healthy was no longer synonymous with being healthy. Many people still remembered President Franklin D. Roosevelt dying of a cerebral hemorrhage on April 12, 1945, and his physician, Admiral Ross McIntire, declaring that it "had come out of the clear sky," even though Roosevelt was known to have had hypertension for more than ten years. (1) It is still debated whether Roosevelt's hypertension and probable complicating heart failure clouded his judgment during the Yalta Conference with Churchill and Stalin only eight weeks before his death. How different would the world have been after the Second World War had the United States, Britain and France liberated Berlin as opposed to the Soviet Union? Similarly, one may wonder what would have happened if Stalin, who also had hypertension, did not sustain a fatal stroke in 1953 and was still alive and in control of the Soviet Union during the Cuban missile crisis.

Before the advent of safe and effective medication to control hypertension, patients took medications only if they were not feeling well. Once these medications became available, asymptomatic patients with hypertension started taking medications to prevent the disastrous effects of hypertension. Doctors acquired a certain aura and mystique. The emphasis shifted from treatment to prevention. Physicians now tried to reach as many healthy people as possible to detect silent hypertension. This paved the way for the detection of several other diseases with long asymptomatic latent periods such as hypercholesterolemia and osteoporosis. It would not be long before a number of screening programs were instituted, and expanded to include breast, prostate, and colon cancer.

Physicians have been able to measure blood pressure for a long time, and the adverse effects of hypertension have been known for quite some time. Before the advent of these medications, there was very little that could be done to manage hypertension. The Kempner diet (2) was tasteless, unappetizing, monotonous, and insipid. Very few patients were able to tolerate it for significant periods. It consisted of boiled or steamed rice in plain water with no salt, and. of fruit (except nuts, dates, avocados, and dried or canned fruit). Water and fluids were restricted. Even among the very few who could tolerate this diet, the reductions in blood pressure were of doubtful significance and probably did not exceed the random spontaneous variations in blood pressure. (3) The only other alternative to the Kempner diet was a bilateral lumbar sympathectomy, a major procedure during that period, and one that was limited to only the relatively young and fit.

The pharmaceutical industry quickly realized that the discovery of effective and safe medications to control hypertension could be a potential gold mine, especially as the benefits of treating hypertension were so convincing. In the mid-1960s, two 'studies, one conducted in England (4) and the other in the USA, (5) demonstrated clearly and beyond any doubt that lowering hypertension is associated with a significant reduction in strokes. In the US Veterans Study, whereas 27 out of 70 untreated hypertensive patients sustained strokes, only 2 out of 70 in the treated group sustained such strokes during the one-year study period. The race was on to develop an effective medication relatively free of adverse effects.

The first group of medication to control hypertension was associated with adverse effects so significant that relatively few patients complied with the prescribed medication, which included methyldopa, reserpine, pentaquine, hydralazine, and guanethidine. Asymptomatic hypertensive patients who felt quite healthy were not likely to continue taking medications that caused them to feel dizzy on standing up, be sedated, be impotent, or have blurred vision, dry mouth, or constipation. Better medications had to be developed.

Diuretics were the first group of drugs to effectively reduce hypertension without causing undue adverse effects. The discovery of diuretics is interesting. The sulphonamides, which were discovered in the 1930s, were routinely used to treat bacterial infections. Some patients noticed that they had a large diuresis after taking this medication. In 1949, William Schwartz, MD, administered sulphonamides to three patients with heart failure. Even though these three patients improved dramatically, Dr. Schwartz concluded that these medications were "too toxic for prolonged or routine use." (6) Fortunately, a research chemist, Karl Beyer, largely through a process of trial and error, modified the formula of the suiphonamide and developed chlorothiazide, a relatively safe but effective diuretic. When administered to ten hypertensive patients, it reduced their elevated blood pressure to almost normal levels within a few days. (7)

Beta-blockers heralded a new era in pharmacology. Propranolol, the prototype of this group of medication, was specifically designed, (8) rather than accidentally discovered, by James Black, a research chemist who subsequently was awarded the Nobel Prize. Interestingly, though, James Black was trying to develop a medication that would block the effects of adrenaline on the [beta]-receptors in the heart for the treatment of angina and was not particularly interested in the treatment of hypertension. The remarkable benefits of [beta]-blockers (9) gave a tremendous boost to pharmacology and the pharmaceutical industry: it was now possible to design medications!

A number of [beta]-blockers with different characteristics such as cardioselectivity and intrinsic sympathomimetic activity became available. This also led to the design of several other compounds with very specific properties such as angiotensin antagonists, angiotensin receptor inhibitors, and calcium channel blockers. Pharmacologists no longer had to wait for medications to be accidentally discovered; they could design, in their own laboratories, medications based on the action profile they wanted.

Because so many medications with similar properties were designed, it became imperative to know which is the best one. It was important to be able to compare the efficacy and safety of these various medications. This is when statisticians made their entrance. For statisticians, hypertension must have been a dream come true: it could be measured to the nearest millimeter of mercury! Systolic blood pressure, diastolic blood pressure, mean blood pressure, pulse pressure -- what a feast! In the feeding frenzy that ensued, numerical systems were developed to quantify how the patients felt. Analogue scales now were used to quantify several subjective parameters such as fatigue, sleepiness, and insomnia. For statisticians and their pinions, the sheer volume of numbers was manna sent from Heaven.

Randomized controlled clinical trials became the battlefields where so many valiant battles between different medications, and different manufacturers, were waged. The smaller the differences between the medications tested, the more sophisticated (or should I say complicated?) were the statistical methods and tests applied. The Art of Medicine was rapidly and inexorably replaced by the Science of Medicine, where statistics were the final arbitrators. An entirely new vocabulary, including power of a study, intention-to-treat analysis, and numbers-needed-to-treat, had to be learned. Clinical impressions and clinical experience were ruthlessly sacrificed on the altar of statistical significance.

Soon another alliance developed: advertisement industry and statisticians. The pharmaceutical industry exploited this alliance to increase the impact of its promotional material. Glossy brochures with superbly illustrated and colorful charts and diagrams were now the basic tools of drug representatives. Subtle differences had to be magnified to justify the promotion of one medication as opposed to another. Statistics ruled above everything else, and could neither be questioned nor challenged. Besides, the statistical methods used were often so complicated that they were beyond the comprehension of most practicing clinicians! Well-trained pharmaceutical representatives could easily browbeat busy clinicians by choosing a few select words acquired from the statistics vocabulary.

The effective management of hypertension also heralded another important change in the doctor-patient relationship. Now, the patient with hypertension has to be treated and followed up essentially for life, and in addition the patient has an important role to play if the hypertension is to be adequately controlled. Now the patient has to assume some responsibility and can no longer be entirely passive. The patient has to be educated about hypertension, its complications and how to avoid them. This education, however, largely dispels the aura and mystique of doctors and the medical profession. Now patients no longer have to take for granted what doctors say. Now the doctors' judgment can be questioned. The patient-doctor relationship has entered a new age!

Ronald C. Hamdy, MD, FRCP, FACP Editor

References

(1.) Messerli F: This day fifty years ago. E Engl J Med 1995; 332:1038-1039

(2.) Kempner w: Treatment of hypertensive vascular disease with rice diet. Am J Med 1948; 4:545-577

(3.) Chasis H: Salt and protein restriction: effects on blood pressure. JAMA 1950; 142:711

(4.) Hamilton M, Thompson EN: The role of blood pressure control in preventing complications of hypertension. Lancet 1964; 1:235-239

(5.) VA cooperative Study Group: Effects of treatment on morbidity of hypertension. JAMA 1967; 202:1028-1033

(6.) Schwartz WB: The effect of sulfanilamide on salt and water excretion in congestive heart failure. N Engl J Med 1949; 240:173

(7.) Freis ED: Treatment of essential hypertension with chlorothiazide. JAMA 1958; 166:137-141

(8.) Black JW, Stephenson JS: Pharmacology of a new adrenergic beta-receptor blocking compound. Lancet 1962; 2:311-315

(9.) Pritchard BNG, Gillam PMS: Treatment of hypertension with propranolol. BMJ 1969; 1:7-15