Reprint from
HYPERTENSIVE CARDIOVASCULAR DISEASE
  Vol. 1    No. 1   Cardiovascular Clinics

The Changing Outlook in
Essential Hypertension

Edward D. Freis, M.D.


HYPERTENSIVE CARDIOVASCULAR DISEASE

Since Goldblatt's classical work on renovascular hypertension there has
been a concerted effort to arrive at the etiological basis of essential hyper-
tension. The work has been successful in uncovering the causes of a few
unusual or rare types of hypertensive diseases, and has led to the realization
that hypertension is a manifestation or response of the body to a variety of
pathogenetic factors. Yet, the cause of essential hypertension, which repre-
sents more than 90 per cent of the hypertensive population, remains obscure.
Indeed, Pickering 1 was led to conclude that no specific abnormality is
present. According to Pickering benign essential hypertension represents
simply the right-hand side of the bell-shaped distribution curve of normal
blood pressures in the general population. The distinction between normal
and hypertensive is quantitative, not qualitative. According to Pickering the
separation of "normal" from "abnormal," using 140/90 mm. Hg as the
dividing line, is purely arbitrary. Blood pressure levels in the general popu-
lation are a continuum and one could equally well take some other arbitrary
value.

Pickering's concept is supported by the accumulated experience of the life
insurance companies 2 who have found that life expectancy worsens with
any elevation of blood pressure above the lowest normal levels. Thus a
group of individuals with blood pressures of 130/80, for example, will not
live as long on the average as another group exhibiting blood pressures of
110/65. These life insurance data also bring out the important point that
blood pressure and mortality are quantitatively related, that is, that the
complications of hypertension are directly related to the absolute level of the
blood pressure.

In the 1930s and 1940s almost all of the emphasis in hypertension research
was directed toward discovering etiological processes. The only drug seri-
ously proposed for controlling the disease was potassium thiocyanate and
this was neither very reliable nor very safe. The only accepted therapy was
sympathectomy and even here it was questioned whether the results merited
the risk and discomfort associated with the operation.

In the late 1940s and early 195Os, however, a concerted chemotherapeutic
attack on hypertension began, first with the Veratrum alkaloids and then
with the ganglion-blocking agent, hexamethonium. Using the latter drug,
Restall and Smirk 3 convincingly demonstrated that it was possible to
reverse many of the manifestations of malignant hypertension. Previously,
I had observed reversal of the malignant phase of hypertension using the
antimalarial drug, pentaquine orally,4 and also Veratrum viride given in
daily intramuscular injections. However, these agents produced almost
intolerable side reactions in the doses required and therefore did not
represent a practical approach to treatment.

Antedating both of these observations, Page had found that pyrogenic
renal extracts were capable of reducing blood pressure and thereby reversing
the malignant phase of hypertension at least in isolated instances. For a
time, the daily administration of pyrogens was an acceptable if somewhat
uncomfortable method for treating malignant hypertension. Even hexa-

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CHANGING OUTLOOK IN ESSENTIAL HYPERTENSION

methonium, the most acceptable and most reliable of the various treatments,
became notorious for the side-effects it produced because of the variety of
symptoms resulting from both sympathetic as well as parasympathetic
blockade. The "hexamethonium man" was characterized as a pale, con-
stipated individual who felt faint in the erect position, suffered from the
cold, was slow to urinate, and was totally lacking in sex.

Despite these crude beginnings, the exciting fact remained that with the
exception of renal failure the observable manifestations of the most severe
type of hypertension were reversible, and even in the case of the former there
was evidence that the rapid progress of the renal deterioration was retarded.
The impetus provided by this discovery quickly led to additional therapeutic
agents. Rauwollia serpentina was introduced from India where its use had
been popularized by Vakil.5 Hydralazine followed soon thereafter,0 and
5 years later the important thiazide diuretics were introduced.? Using
combinations of these less-potent but better-tolerated agents there evolved
a practical, tolerable, and reasonably effective therapy for controlling
elevated blood pressure.

Encouraged by the success in treating malignant hypertension, investi-
gators began to consider a broader attack on the problem. It seemed a
reasonable hypothesis that all of the disabling complications of hypertension
such as cardiac enlargement, cerebral hemorrhage, dissecting aneurysm of
the aorta, and nephrosclerosis were the direct result of the elevated blood
pressure per se and that if one could control the hypertension early these
major complications might be prevented. It even seemed possible that the
incidence of atherosclerotic complications which are so common in hyper-
tension, principally myocardial infarction and cerebrovascular thrombosis,
could be reduced considerably if the blood pressure were maintained at
normal levels from an early stage of the disease.

There was much indirect evidence to support this hope. An inordinately
frequent association between hypertension and cerebrovascular and coronary
thrombosis has been repeatedly demonstrated, most recently in the Framing-
ham study.* Nature has also provided several crucial experiments in man
demonstrating the causal relationship between elevated blood pressure and
the development of atherosclerosis. For example, the low pressure pul-
monary arterial system is almost never the site of atherosclerotic lesions; yet,
in the presence of longstanding and severe pulmonary hypertension, as
occurs with large intraventricular septal defects, atherosclerosis is common.
In coarctation of the aorta, atherosclerotic lesions are prevalent in the high
pressure area above the coarctation, whereas in the low pressure area below,
the aorta may be almost completely spared. Most significantly, Deming 9
showed that experimental atherosclerosis in rats was considerably worsened
if the animals were made hypertensive, but that this acceleration could be
prevented if they were simultaneously treated with antihypertensive agents.

Using a working hypothesis that antihypertensive therapy prevents the
complications of hypertension from developing, investigators began to col-
lect evidence that would bear on this question. Unfortunately, the early

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reports left much to be desired in the way of experimental design and,
therefore, were not very convincing. Most of these reports compared a
presently treated series with case records from the decade of the 1940s prior
to the advent of effective antihypertensive drugs. It is little wonder that the
results were conflicting and often reflected the bias of the observer. Thus,
Leishman 10 reported a significant reduction in mortality in the treated
patients with benign essential hypertension, whereas Perera I1 found no
difference in mortality in middle-aged patients with moderately severe
essential hypertension. Hodge, McQueen, and Smirk 12 used as their control
the patients who refused treatment. This at least placed the control group
in the same era as the treated patients but introduced an unknown bias since
the untreated group probably were more neglectful of their health and were
in any event essentially lost so far as control of their future therapy was
concerned. These authors reported a significant reduction in mortality in
Keith-Wagner Groups I and II as a result of treatment.

The first controlled trial was that reported by Hamilton 13 who alternately
assigned 61 patients with diastolic blood pressures of 110 mm. Hg or higher
to active treatment and placebo. Of these, 30 were treated with antihyper-
tensive agents while 31 were not. Over an g-year period of followup, sixteen
of the untreated patients had complications, primarily strokes, as compared
to five of the treated group. A prospective, randomized control study was
carried out by Wolff and Lindeman I-* in 87 patients. Twelve per cent
defaulted. Over a 2-year period the incidence of morbid events in the
treated patients was one third of that observed in the placebo group. Both
of these studies were concerned with essential hypertension of more-than-
average severity. Definitive evidence on the value of treatment in the .
"garden variety" mild case of essential hypertension still was lacking.

In 1963, a group of interested investigators in the Veterans' Administra-
tion 16 decided to initiate a carefully designed, rigorously conducted multi-
clinic trial on the effects of drug treatment on morbidity in both mild and
moderately severe hypertension. The population selected was the group of
patients with diastolic pressures from 90 to 130 mm. Hg, who had no
evidence of severe hypertensive complications.

It was realized that the patient who does not take his medications regularly
could seriously distort the results. Therefore, special precautions were taken
to recognize and exclude such patients from the study. This was done by
instituting a Z- to 4-month prerandomization trial period, during which time
pill counts and urine fluorescence tests were carried out. The latter test was
based on the ability of riboflavin to cause urinary fluorescence when the
urine was viewed under ultraviolet light. Riboflavin was incorporated in
the placebos that were administered to all patients during the trial period.
Only those patients who kept their clinic appointments, returned an accept-
able number of tablets, and exhibited riboflavin fluorescence in their urine
were accepted in the trial.

Following the trial period the accepted patients were randomly assigned,
double blind, either to active drugs or to placebos. The active drug regimen

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CHANGING OUTLOOK IN ESSENTIAL HYPERTENSION

consisted of hydrochlorothiazide, reserpine, and hydralazine. The effective-
ness of this regimen in reducing blood pressure was attested to in the patients
with moderate hypertension by the fact that whereas the placebo group
exhibited no significant change in blood pressure the average reduction in
the actively treated patients was 43/29 mm. Hg.

After the study had been in progress for approximately 2 years it became
apparent that a high incidence of complications was occurring in the seg-
ment of the placebo-treated patients whose entrance diastolic blood pressures
averaged 115 mm. Hg or higher .I0 Of seventy placebo-treated patients with
such levels of blood pressure on entrance, twenty-seven severe complicating
events developed as compared to only two in the seventy-three actively
treated patients. Four deaths occurred in the placebo group and none in the
active group. The deaths were unusual in that two were associated with
dissecting aortic aneurysm, one with ruptured atherosclerotic aneurysm of
the abdominal aorta, and only one with the more common cause of sudden
death probably due to myocardial infarction. The most common nonfatal
complication in the "severe" group was the development of signs of malig-
nant hypertension, that is, further elevation of blood pressure and the
appearance of hemorrhages, "cotton wool" exudates, or papilledema in the
optic fundi. All of the latter responded promptly with clearing of the
malignant signs when known active treatment was started. Other less
frequent complications in the placebo-treated patients were congestive heart
failure, increasing azotemia, cerebrovascular accidents, myocardial infarc-
tion, and severely elevated blood pressure without neuroretinopathy. The
two complications occurring in the actively treated patients was one instance
of cerebrovascular thrombosis and one patient who developed multiple drug
toxicities, which later disappeared when his drug regimen was changed.

It is evident from the preceding study that patients with diastolic pressures
averaging 115 mm. Hg or higher during repeated office visits represent an
especially high-risk group who tend to develop complications more spe-
cifically related to hypertension than to atherosclerosis. The evidence that
treatment was effective in this group in preventing complications was over-
whelming. Even if one accounts for the 7 per cent dropouts, and assumes
that all of those who dropped out on active drugs developed a morbid event
whereas none of the placebo-treated dropouts did, the evidence favoring
treatment would still be significant with a probability of less than 1 in 1,000
that the difference could have occurred by chance.

In the "milder" group of hypertensive patients with entrance diastolic
blood pressures averaging less than 115 mm. Hg, no highly significant
difference has yet developed between the treated and placebo groups over
an average followup period of approximately 3 years. Further, the types of
complications developing in this milder group differ from those in the more
severe group in that they are predominantly atherosclerotic with sudden
death and myocardial infarction being especially prominent. Because
atherosclerotic complications predominate in these milder cases one would

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expect that if a significant effect of treatment will appear it will take a
considerable period of time to become evident.

It has also been observed that the pattern of fatal complications has been
changing in the last 15 years and that the difference is most likely due to
antihypertensive treatment. Whereas, in the 1940s and previously the most
common causes of death in hypertension were congestive heart failure,
uremia, and cerebral hemorrhage, today the most frequent cause is coronary
artery disease including sudden death which in most instances is due to
ventricular fibrillation secondary to coronary artery disease. Hodge and
Smirk Ii reported recently that during the years 1959 to 1964 coronary artery
disease accounted for approximately half of all deaths related to hyperten-
sion. Stroke was the second most common cause of death, accounting for
about one fourth of the deaths related to hypertension. Deaths due to
unrelated causes, such as cancer, accounted for 18 per cent of all deaths, a
considerable rise over prior decades. Deaths from uremia occurred in only
10 per cent of the total while congestive heart failure accounted for only
6 per cent of the total deaths. Now that acceleration of hypertension is
prevented by antihypertensive therapy it appears that the atherosclerotic
complications have emerged as the most important remaining problem in the
treatment of the hypertensive patient.

While still the most difficult and most resistant form of hypertension to
treat it has become apparent in recent years that even the patients with
renal failure have a better outlook than ever before because of antihyperten-
sive drug treatment. A recent study by Woods and Blythe * indicates that
many of their patients with azotemia can live in relative comfort for years
providing one is successful in controlling the blood pressure. Because hyper-
tension appears to be the important pathogenetic mechanism in producing
nephrosclerosis, it seems probable that adequate reduction of blood pressure
will arrest or at least retard the further progression of the arteriolosclerotic
process.

I have not had as much success in treating the uremic hypertensive patient
with antihypertensive drugs alone. Particularly in the uremic patient with
malignant hypertension only a moderate prolongation of life generally has
been obtained, in contrast to the nonuremic patient with malignant hyper-
tension where survivals as long as 20 years have been personally observed
following antihypertensive treatment.  On the other hand, several almost
terminal patients with uremia secondary to malignant hypertension have
had their useful lives preserved by renal transplantation, which may provide
the final last-ditch hope for these most advanced cases.

It is becoming increasingly apparent that antihypertensive drug treatment
represents one of the great medical triumphs of the current era. This is
doubly significant in that it represents the first successful therapeutic attack
on the so-called "degenerative" cardiovascular diseases of middle and old age.
The value of treatment in patients with diastolic blood pressures averaging
above 115 mm. Hg has been firmly established. Although definitive proof is
still lacking for the treatment of the milder cases, it seems entirely reason-

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able, in view of the available evidence, that reduction of the blood pressure
in an early stage of the disease will prevent the complications of hypertension
from developing, including many of the atherosclerotic complications. An
important remaining question is, at what level of blood pressure should one
begin treatment? If the life insurance statistics are heeded, perhaps treat-
ment should be instituted at diastolic levels presently regarded as normal.
However, before this is done antihypertensive drugs must be made safer,
cheaper, and more easily regulable than they are today.

References

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