In 1949 Freis was appointed Assistant Chief of the Veterans Administration Hospital Medical Service in Washington, DC. (He became Chief of the Service in 1954 and in 1959 was appointed a Senior Medical Investigator.) Concurrently he joined the clinical teaching staff of Georgetown University School of Medicine, and directed the Cardiovascular Research laboratory there until 1965. He also headed the Hypertension Clinic at the Georgetown University Medical Center from 1950 to 1960. In these posts Freis continued his laboratory studies on hemodynamics and his clinical studies on drug treatment of hypertension.
In the late 1940s a new group of drugs, the ganglionic blocking agents, expanded the possibilities for treating hypertension. Ganglion blockers interfere with the nerve impulses from the brain that constrict blood vessels, thus achieving the same effect as surgical sympathectomy. Among these were hexamethonium and reserpine. Hexamethonium had been developed following earlier research with tetraethylammonium, a short-acting ganglion blocker. Reserpine is the active alkaloid in Rauwolfia serpentina, a plant long used by Indian physicians to treat mentally disturbed patients. While reserpine was also used in the United States for psychiatric disorders, beginning in the 1950s, it was also shown to be effective in lowering blood pressure. During the following decade other such drugs, such as pentolinium, guanethidine, and methyldopa were also found to be effective. Hydralazine, a vasodilator (which dilates blood vessels, allowing more blood flow), was also in use by the late 1950s. In their studies on these drugs, Freis and his colleagues also found that they greatly helped in cases of congestive heart failure, by easing the load on the left ventricle and increasing cardiac output. Some of the newer drugs had the added benefit of being more selective in their action, e.g., guanethidine effectively blocked the sympathetic ganglia without also inhibiting parasympathetic functions and causing side effects such as dry mouth and constipation.
The most important breakthrough in the drug treatment of hypertension, however, came in the mid-1950s, with the introduction of an orally effective diuretic, chlorothiazide, developed by chemists at Merck & Co. Thiazide diuretics effectively reduced blood pressure in hypertensive patients and produced the same blood volume changes as a low-salt diet (and were much more acceptable to the patients than such diets). The diuretics often worked well alone, but also enhanced the effects of other hypertension drugs. This meant that blood pressure could be controlled with smaller doses of the drugs, and thus with fewer side effects. For the first time, it became possible to control high blood pressure in many cases without serious discomfort or inconvenience to patients. This in turn increased the chances that patients would continue treatment for the long term.
While great strides had been made in controlling high blood pressure with these medications, it still remained to be proven that doing so would keep patients healthier or keep them alive significantly longer. Most of the patients in Freis's clinical studies suffered from malignant hypertension, in which serious symptoms could already be seen. Freis and his colleagues had shown that some of these--congestive heart failure, kidney damage, and so on--could be at least partially reversed, and that some patients could return to work and survive in reasonably good health for a number of years. But malignant hypertension has a different pathology from what was then called "benign essential" hypertension, which is far more common. Benign essential or primary hypertension is slowly progressive and is characterized by arteriosclerosis (artery hardening) and accelerated atherosclerosis (build-up of hard plaques inside arteries). The demonstrated effectiveness of treatment in malignant hypertension could not be used as proof of effectiveness in essential hypertension. Treated patients with essential hypertension did seem to have fewer subsequent cardiovascular problems and longer life spans when compared to patients in the pre-drug era or to patients who refused drug treatment. However, because of the lack of valid controls, this type of evidence was not generally accepted, and until the 1970s the drug treatment of essential hypertension remained a matter of controversy. In the tradition of scientific medicine, many physicians were skeptical about treating a condition whose fundamental causes were unknown. Some claimed that lowering the blood pressure was merely "treating the manometer instead of the patient." Proponents of antihypertensive treatment needed more definitive evidence, which could be obtained only from a well-controlled, prospective therapeutic trial.
In 1956, a group of physicians in Veterans Administration Hospitals organized a cooperative study group to evaluate antihypertensive agents under well-controlled conditions. The initial trials were concerned with the comparative effectiveness of single agents and combinations of drugs. The study, modeled on a recent VA study of anti-tuberculosis drugs, was one of the first placebo-controlled double-blind clinical trials done in the United States. In controlled trials, one group of patients is given the treatment being evaluated, while another group of similar size is given a placebo; "double-blind" means that neither the patients nor the staff administering the treatment knows which group is which, so that responses to treatment cannot be influenced by prior knowledge. This methodology has since become standard in clinical trials, but was not widely used at the time. The VA, which had pioneered the use of such methods, had several biostatisticians on staff who assisted Freis in designing the drug evaluation study. In 1962, it was decided to undertake another controlled trial to determine the effectiveness of antihypertensive agents on prevention of morbidity and mortality in patients with moderate to severe hypertension.