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`Copyright © 1979 by Annual Reviews Inc. All rights reserved
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`VALIDITY OF THERAPY
`FOR MILD HYPERTENSION
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`.7307
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`Edward D. Freis, MD.
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`Veterans Administration Hospital and Department of Medicine,
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`Georgetown University School of Medicine, Washington, DC 20422
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`Hypertension affects at least one in ten adults in nearly every country in the
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`world. It ranks third only to atherosclerosis and cancer as a cause of death.
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`It is also a leading risk factor in atherosclerotic complications such as
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`myocardial infarction, sudden death, and atherothrombotic stroke. Hyper
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`tension, therefore, is a double-edged sword. It produces complications spe
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`cifically related to hypertension per se, such as hemorrhagic stroke,
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`congestive heart failure, and renal failure, and, in addition, it aggravates and
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`accelerates atherosclerosis.
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`RATIONALE OF TREATMENT
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`are still unknown. hypertension The ultimate cause or causes of essential
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`Except for rare secondary forms the goal in treating hypertension is not to
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`cure the disorder but to control the blood pressure and, thereby, prevent
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`hypertensive complications. This approach is based on the theory, which we
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`can now regard as established from both animal experiments and clinical
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`trials, that the major cardiovascular complications associated with hyper
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`tension are the result of damage produced directly by the elevated blood
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`pressure. It has not been demonstrated, however, that reducing the elevated
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`blood pressure will retard the development of the atherosclerotic complica
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`tions often associated with hypertension.
`The cardiovascular changes that characterize hypertension appear to be
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`secondary to elevated blood pressure (1). Fibrinoid necrosis and hyalinosis
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`of the arterioles probably represent adaptations to the increased blood
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`pressure; cerebral microaneurysms, a frequent source of cerebral hemor-
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`81
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
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`82 FREIS
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`rhage, may result from yield stresses produced by the hypertension; and left
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`ventricular hypertrophy and dilatation represent adjustment to an increased
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`afterload. The predisposition to atherosclerosis may be due to injury to the
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`of antihyper(2). The rationale arterial intima caused by the hypertension
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`tensive treatment, therefore, is to reduce the blood pressure to a level where
`these damaging effects will not occur.
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`EVIDENCE IN ANIMALS
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`The complications of hypertension can be completely prevented by antihy
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`pertensive drug treatment in the spontaneously hypertensive rat (3). The
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`Kyoto strain of spontaneously hypertensive rats develop a progressive ele
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`vation of blood pressure with increasing age; after one year they begin to
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`die from cardiovascular complications associated with the hypertension. If
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`antihypertensive agents are added to the drinking water their blood pres
`sures remain at low levels and they develop none of the cardiovascular
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`complications associated with hypertension. Furthermore, their life span
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`increases by more than half that of the untreated animals and becomes the
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`same as that of a normal rat (4). The treated animals tolerated the drugs
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`and appear as very well; they gain weight normally, bear normal litters,
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`active and healthy as normotensive untreated rats.
`The cardiovascular complications occurring in spontaneously hyperten
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`sive rats are in many respects similar to those found in hypertensive patients
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`and include hemorrhagic stroke, congestive heart failure, and renal damage.
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`The rat lesions differ from those in man, however, in one important respect.
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`The rat is resistant to atherosclerosis and seldom exhibits such lesions even
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`when plasma cholesterol levels are increased by diet. The complete protec
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`tion from cardiovascular lesions provided by treatment in the rat, therefore,
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`applies only to hypertensive complications and not to atherosclerotic le
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`sions, which rarely occur in the spontaneously hypertensive rat.
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`EARLY CLINICAL TRIALS
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`The evidence in man is based largely on controlled clinical trials. The first
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`of both trial was carried out by Hamilton and co-workers (5) in 61 patients
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`sexes with severe essential hypertension. Patients were assigned alternately
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`to either active drugs or to no treatment. Over a follow-up period of two
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`to six years, there were significantly fewer complications in the treated
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`patients than in the untreated group. Almost all of the treated patients who
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`developed complications failed to achieve a reduction of diastolic blood
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`pressure below 110 mm Hg. Most ofthe complications were of the hyper
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`tensive rather than the atherosclerotic type.
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-2
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`THERAPY 83
`HYPERTENSION
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`A controlled trial carried out by Wolff & Lindeman (6) in 87 patients with
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`moderate to severe
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`indicated that over an average
`follow-up
`hypertension
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`period of two years the incidence of morbid events in the treated patients
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`was one third that observed in the placebo group.
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`Carter (7) carried out a prospective randomized trial in 97 hypertensive
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`stroke survivors. Over a period of three to five years 46% of the control
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`patients died as compared to 26% of the treated group. Nonfatal strokes
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`occurred in 23% of the control group as compared to 14% of the treated
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`patients. However, in a well-controlled trial in patients with mild hyperten
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`sion who had survived a single stroke, Hoobler and his associates (8) found
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`no significant protection against subsequent strokes by treatment.
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`THE VETERANS ADMINISTRATION TRIAL
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`The largest scale controlled trial was that carried out by the Veterans
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`Administration Cooperative Study Group (9-11). This randomized, dou
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`ble-blind study included 523 male hypertensive patients, average age 49
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`years, whose initial diastolic blood pressure ranged between 90 and 129 mm
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`Hg (average of two clinic visits immediately preceding randomization).
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`Many of the patients showed evidence of end-organ disease and all main
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`tained a diastolic blood pressure of 90 mm Hg or higher during a week's
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`hospitalization. Patients were randomly assigned, double-blind either to a
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`combination of hydrochlorothiazide, reserpine, and hydralazine or to place
`bos of these drugs.
`The trial was terminated early in the subgroup of 143 patients with initial
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`diastolic blood pressure averaging between 115 and 129 mm Hg (9). Of the
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`70 patients in the control group 27 developed major cardiovascular compli
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`cations over an average follow-up period of only 20 months. Most of these
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`complications were of the hypertensive rather than the atherosclerotic type.
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`In the treated group of 73 patients there was only one major cardiovascular
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`event, which was an atherothrombotic stroke. Two others were removed
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`from the study because of side effects of the antihypertensive drugs.
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`There remained in the trial 380 patients with mild to moderate elevations
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`of blood pressure prior to randomization averaging between 90 and 114 mm
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`Hg (10). These patients were followed for an average period of 3.3 years and
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`some were followed for more than f ve years. Nineteen of the control
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`patients died of cardiovascular complications as compared to eight in the
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`treated group, a ratio of more than two to one in favor of treatment. All
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`of the deaths occurring in the treated group of patients were related to
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`atherosclerotic complications whereas the deaths in the control group were
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`due to either hypertensive or atherosclerotic events. Since many of the
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-3
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`84 FREIS
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`patients had hypertension of long duration, it would be expected that they
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`already had extensive atherosclerosis at the time of entry.
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`The incidence of all morbid events both nonfatal as well as fatal was
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`assessed by the life-table method of analysis (Figure 1). This indicated
`that
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`over a five-year period the risk of developing a major cardiovascular compli
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`cation was reduced from 55% in the control group to 18% in the treated
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`patients, a ratio of approximately three to one in favor of treatment. In
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`addition to these morbid events there were 20 patients, all in the control
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`group, who exhibited progression of their hypertension to above 120 mm
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`Hg diastolic blood pressure and who were removed from the trial before
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`they developed a major complication.
`The effectiveness of treatment was definitely related to the initial height
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`of the blood pressure (10, 11). The striking effect of treatment in the group
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`ALL MORBID EVENTS
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`Estimated cumulative incidence of morbidity over a
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`five-year period as calculated by life-table method.
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`10%
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`1
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`3
`2
`4
`Years of Observation
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`5
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`Figure 1 Graph of estimated five year morbidity in the control vs the treated group of 380
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`male patients with initial diastolic blood pressure in the range of 90- 114 mm Hg inclusive.
`(Data from Ref. 10),
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-4
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`THERAPY 85
`HYPERTENSION
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`with severe hypertension has already been described. The patients with mild
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`to moderate hypertension were subdivided into two groups,
`those with
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`initial diastolic levels of 90-104 mm Hg and the group with diastolic blood
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`pressures of 105-114 mm Hg at entrance into the study. Treatment was
`considerably
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`more effective in the latter than in the former or mild group.
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`In the patients with moderate hypertension cardiovascular complications
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`were four times higher in the control than in the treated patients. But, in
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`the mild group the difference was less than two to one in favor of treatment.
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`Because of this minor difference in incidence of complications and also
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`because of the relatively small size of the mild subsample, the effectiveness
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`of treatment for mild hypertension was left in doubt. It is worth noting,
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`however, that progression to a more severe stage of hypertension and the
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`development ofleft ventricular hypertrophy were not included as assessable
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`morbid events. If they had been included the results would have indicated
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`a greater effectiveness of treatment.
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`US PUBLIC HEALTH SERVICE HOSPITALS TRIAL
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`There are, as yet, no other controlled trials on mild hypertension in which
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`the data have been published in full. The results of the study in the United
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`States Public Health Service Hospitals conducted by Dr. W. McFate Smith
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`have been published only in preliminary form (12). Their patients numbered
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`389 and were followed for as long as seven years. In contrast to the Veterans
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`Administration study, none of their patients exhibited evidence of end
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`they tended Furthermore, organ disease at the time of entry into the study.
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`to be younger with an average age of 44 years as opposed to 49 years in the
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`Veterans trial. The trial also included females as well as male patients.
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`While they admitted patients with diastolic levels ranging between 90 and
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`115 mm Hg, the majority of the patients had rather mild hypertension as
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`indicated by the average admission blood pressure of 148/99 mm Hg.
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`Over the seven-year period of follow-up, hypertensive complications oc
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`curred more than twice as frequently in the control as in the treated group.
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`Most of the preventable complications appeared to be related to electrocar
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`diographic manifestations ofleft ventricular hypertrophy. The incidence of
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`atherosclerotic events, however, including those related to coronary artery
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`disease, was essentially the same in the treated and control patients.
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`CORONARY ARTERY DISEASE
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`Hypertension even of mild degree aggravates and accelerates atherosclero
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`sis (13). Atherosclerosis appears to be a response to injury to the arterial
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
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`86 FREIS
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`endothelium (2) that in many instances could be the result of the hyperten
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`sion. Hypertension also causes structural changes in the arterial walls such
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`as disruption of the elastic lamellae and proliferation of fibrous and collage
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`nous connective tissue with resulting loss of distensibility of the arterial
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`wall. The distention of arteries secondary to hypertension also may stretch
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`the endothelium to make it more permeable to lipids. The question of
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`reversibility of these changes with continued reduction of blood pressure
`has not yet been settled.
`In the Veterans Administration trial, treatment was highly effective in
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`preventing the complications that are specifically related to the hyperten
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`sion itself as opposed to atherosclerotic complications. Hypertensive com
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`plications such as cerebral hemorrhage, renal functional deficits, congestive
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`heart failure, and dissecting aortic aneurysm occurred exclusively in the
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`control group. On the other hand, atherosclerotic events such as myocar
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`dial infarction, atrial fibrillation, and heart blocks appeared with approx
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`imately the same frequency in the control and treated patients. Smith
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`found essentially the same differential effect of treatment on hypertensive
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`as compared to atherosclerotic complications in patients with mild hyper
`tension.
`It might be argued that many of the patients entering the Veterans study
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`were not representative of the general hypertension population because of
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`age, hypertension oflong standing, and evident target-organ disease. There
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`fore, many of them may have had extensive sclerosis of their coronary
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`arteries at the time of entry and the risk of myocardial infarction was great
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`regardless of the level of blood pressure. However, as noted above, Smith's
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`study in patients with uncomplicated mild hypertension provides similar
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`results; the incidence of complications due to coronary artery disease was
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`not significantly different in the treated and control groups (12).
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`Neither the Veterans Administration study nor the Public Health Service
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`Hospital trial were specifically designed to answer the question of the effect
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`of treatment in preventing myocardial infarction. Larger scale studies cur
`rently underway in the United States and other countries should provide
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`more definitive evidence. For the present, it seems best to keep an open mind
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`on the subject, although the prospects for achieving significant benefit with
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`blood pressure reduction alone do not appear promising.
`Myocardial infarction is far and away the leading cause of disability and
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`death in patients with mild hypertension. Such patients rarely develop the
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`hypertensive complications that are so spectacularly benefited by treatment.
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`The usual cause of death in untreated mild hypertension is either myocar
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`dial infarction or sudden death; if the patients survive to old age they may
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`also die of atherothrombotic stroke.
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-6
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`HYPERTENSION THERAPY 87
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`DECISION TO TREAT MILD HYPERTENSION
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`Mild hypertension is herein defined as a diastolic blood pressure in the range
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`of 90-104 mm Hg inclusive (fifth phase of Korotkoff sounds) over three or
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`more successive office or clinic visits. The reasons for stipulating at least
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`three visits is that the readings on the initial visit may be misleadingly high
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`and also that blood pressure characteristically fluctuates over a wide
`range.
`It must be admitted at the outset that our knowledge of the value of
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`treatment in mild hypertension is fragmentary. Yet, it is far and away the
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`most frequently encountered form of hypertension in clinical practice. Ac
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`Health Survey, the prevalence of mild hypertension
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`cording to the National
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`is approximately five times higher than all other forms combined (14). The
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`problem is ever with us and we must, therefore, make as prudent decisions
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`as possible. To decide to treat all individuals with diastolic levels of 90 mm
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`Hg or above would involve about 20 million patients in the United States
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`(estimated number with such average levels over three visits), who would
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`be receiving antihypertensive agents on a life-long basis. The cost and risks
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`of such an undertaking are staggering. Before doing so we must be certain
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`that the therapeutic program is justified. If drug therapy is of only question
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`able value we should ask whether its benefits justify the expense, inconve
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`nience, and possible toxic side effects associated with treatment. The
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`common thread that ties together the results of the various therapeutic trials
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`is that treatment is highly effective against hypertensive complications but
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`is only questionably effective against atherosclerotic complications.
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`Treatment, therefore, is definitely indicated whenever the risk of hyper
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`tensive complications is present. Also, the several controlled trials indicated
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`that approximately 1-2% per year of mild hypertensives progress to a more
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`severe stage. In the Veterans Administration trial this progression occurred
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`mostly in younger patients. Also, the evidence is clear that electrocardio
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`graphic changes indicative of left ventricular hypertrophy are favorably
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`influenced by treatment.
`Patients with mild hypertension who are at greatest risk of developing
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`hypertensive complications or progression of hypertension are those with
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`the following characteristics: (a) presence of target-orgaQ disease such as
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`L VH, Group II fundi, etc; (b) age below 45 years; (c) black race; (d) males;
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`(e) diastolic pressure above 95 mm Hg on each of three pretreatment visits;
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`and if) family history of severe hypertensive disease.
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`The more of these hypertensive risk factors that are present, the greater
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`is the indication for treatment. Also, the more closely the average diastolic
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`blood pressure approaches 105 mm Hg, the more likely it is that treatment
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-7
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`88 FREIS
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`will be undertaken. Both the height of the blood pressure and the number
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`of other risk factors present are essential components in the therapeutic
`formula.
`The remaining individuals with mild hypertension are mostly those above
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`the age of 45 who are without symptoms. This represents the largest group
`of the hypertensive
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`population and their chief risk is the development of
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`atherosclerotic complications. Although there is no proven effective preven
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`tive treatment for these patients it would seem prudent to utilize whatever
`knowledge we have short of exposing them to drugs. Such "hygienic"
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`measures would include low-sodium and low-saturated-fat diets, regular
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`exercise, weight reduction of the obese, and discontinuation of cigarette
`smoking.
`if future therapeu
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`A more aggressive approach will, of course, be justified
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`tic trials produce evidence that antihypertensive drug treatment protects
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`against the complications of coronary artery disease. Several recent con
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`trolled trials have indicated that beta-adrenergic-blocking drugs reduce the
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`risk of myocardial infarction or sudden death (15, 16). While these studies
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`need confirmation, they suggest that reducing the adrenergic drive to the
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`heart may have protective effects independent of, or in addition to, simple
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`reduction of blood pressure.
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`SUMMARY
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`Hypertensive patients are candidates for drug therapy when they are at risk
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`of developing hypertensive complications. There is at present no evidence
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`that drug therapy is effective when the risk is limited only to atherosclerotic
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`complications. However, the question must be left open because of insuffi
`cient data.
`Potential benefits of drug therapy must be weighed against potential risks,
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`expense, and inconvenience. Patients at high risk of hypertensive complica
`tions such as young black males probably should be treated even if the
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`hypertension is mild. On the other hand, in patients with mild hypertension
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`who are not at such risk it would seem prudent to utilize dietary and
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`hygienic measures that may reduce atherosclerotic changes and that are not
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`harmful in themselves. Whatever decision is made regarding drug treatment
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`the patients must be followed at regular intervals because of the tendency
`for some to progress to a more severe stage.
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-8
`IPR2016-00379
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`Literature Cited
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`HYPERTENSION THERAPY 89
`
`2. Ross, R., Glomset, J. A. 1976. Ther.a
`
`1. Pickering, G. W. 1968. High Blood
`
`P7�ure, pp. 310-13, 351-52. �ew
`
`York: Grone & Stratton. 717 pp.
`2nd ed.
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`morbidity: Results in patients with dias
`
`tolic blood pressures averaging 11 5
`through 129 mm Hg. J. Am. Med. As
`soc. 202:1028-34
`10. Ibid 1970. II. Results in patients with
`
`N. Eng. J.
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`diastolic blood pressure
` 90
`thogenesis of atherosclerosis.
`
`through 114 mm Hg. J. Am. As
`Med. 295:369-77
`soc. 213:1143-52
`3. Freis, E. D., Ragan, D., Pillsbury, H.,
`
`11. Ibid 1972. III. Influence of age, diastolic
`Mathews, M. 1972. Alteration in the
`
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`pressure and prior cardiovascular dis
`
`course of hypertension in the spontane
`
`ously hypertensive rat. Cire. Res.
`
`ease; further analysis of side effects. Cir
`culation 45:991-1004
`41:1-7
`4. Freis, E. D., Ragan, D. 1976. Treat
` Co
`12. US Public Health Service
`Study Group. w. M.
`operative
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`ment and longevity in spontaneously
`
`(Chairman). 1977. Treatment of mild
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`hypertensive rats (SHR). Clin. Exp.
`Pharmacol Physiol Suppl. 3, pp. 75-78
`
`
`hypertension. Results of a ten-year in
`
`tervention trial. Cire. Res. 40: Suppl. I,
`
`5. Hamilton, M., Thompson, E. �., Wis
`pp.98-105
`
`neiwski, T. K. M. 1964. The role of
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`blood pressure control in preventing
`13. Freis, E. D. 1969. Hypertension and
`
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`atherosclerosis. Am. J. Med. 46:735-40
`
`
`complications in hypertension. Lancet
`1:235-38
`14. �ational Health Survey. 1966. Hyper
`6. Woltf, F. W., Lindeman, R. D. 1966.
`
`tension and hypertensive heart disease
`Effects of treatment in hypertension:
`in adults. 1960-62, US Dept. Health,
`
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-9
`IPR2016-00379