There have been two clinical trials in hypertension that have directly
addressed the question of whether we would reduce hypertensionrelated
morbidity and mortality by more aggressive compared with less
aggressive antihypertensive therapy (7,8) (Table 1-4). The first of these
was the Hypertension Detection and Follow-up Program (HDFP) (7).
This trial was begun in 1972 in the United States and was completed
in 1979. The investigators reflected the American, but not the European
or Australian, view that it was not ethical after the VA trial was
completed to do a placebo-controlled study in hypertensive patients
with an elevated DBP. Therefore, HDFP compared the results of treating
hypertensive patients to a goal (<90>100
mmHg or a 10 mmHg reduction if entry DBP was 90–99 mmHg) vs
usual care. Rather than having a placebo as the control, HDFP compared
a group called Stepped Care (SC) that was treated with active medication
(a diuretic followed by methyldopa, hydralazine, and guanethidine, if
needed), and treated to that goal, with a control group whose members
were cared for by their primary physicians and treated however vigorously
their physicians deemed necessary, the so-called referred care
(RC) group. The SC group really should have been called Special Care
because these individuals were seen very frequently and received care
and surveillance for many problems other than hypertension. The RC
group should have been called Routine Care because these individuals
were seen only at the HDFP clinical centers twice in the 5 yr and were
otherwise treated per their physicians’ routine. The participants in RC
actually received similar medication but fewer were treated and those
who received treatment were certainly less aggressively managed. At
the end of the trial, the participants in the SC group had their DBP
lowered to an average of 83 mmHg compared with an average of 89
mmHg in the RC group. All-cause mortality, the primary end point
in HDFP, as well as cardiovascular mortality were both statistically
significantly reduced in the SC vs RC group. The benefit was seen in
all demographic groups except for white women, whose absolute risk
was very low. HDFP did not enroll enough white women to be able
to show benefit in these relatively low-risk individuals.
The second study looking at the DBP goal of therapy was the
Hypertension Optimal Treatment (HOT) study, completed in 1998 (8).
HOT was specifically designed to determine whether hypertensive
patients ages 50–80 with elevated DBP (100–115 mmHg at baseline)
would do better if DBP was lowered to <80 mmHg, vs <85 vs <90
mmHg. HOT was done in a Prospective Randomized Open Label
Blinded Evaluation design. In such trials, the drug administered is
known to investigators and participants but all end points are evaluated
by a committee blinded to the drug actually used or, in this case, the
BP goal. All subjects received a dihydropyridine calcium antagonist
started at a low dose (5 mg of felodipine) followed by either an ACE
inhibitor or -blocker at low dose, if more therapy was needed to
achieve the predetermined goal. The investigator decided which class
of drug to add. If the goal was still not reached, further increases in
the dose of felodipine to 10 mg (step 3) and then increased doses of
the second drug were mandated (step 4). Finally, a diuretic or other
therapy was added (step 5) to achieve the study goal. The cohort
enrolled was very large (nearly 19,000) and the follow-up was planned
to be approx 2–2.5 yr (40,000 participant-yr). The study was extended
to an average follow-up of 3.7 yr (71,000 participant yr) when the
event rate in all groups was substantially less than predicted. These
participants were practically immortal.
The main result in HOT was disappointing to some because there
was no difference in the rates of study end points between these groups.
The optimal BP was calculated to be 138/83 mmHg, a strikingly similar
finding to that of the HDFP. There was no evidence of an on-treatment
DBP under which the event rate rose (i.e., there was no J-point ascertained).
In the 1501 subjects with type 2 diabetes, there was a highly
statistically significant trend (p < 0.001) for reduced cardiovascular
(CV) events when DBP was lowered to <80 mmHg. This finding
supports the concept that the lower the achieved DBP the better, especially
in those with a high absolute risk for events.
In my view, HOT should not be viewed as a failed study. More than
90% of the cohort, primarily recruited from private practices in 26
countries, had their DBP reduced to <90 mmHg and were able to
maintain that level for several years. In fact, more than 50% of those
randomized to be treated to a DBP of <80 mmHg achieved this very
aggressive goal. The treatment used was conventional and simple to
implement. Ordinary doctors treating ordinary patients with ordinary
medicines achieved the study BP goals and did so without causing
harm. To accomplish this level of success, combination therapy was
usually necessary. Only about one third of those who were to be treated
to <90 mmHg got to that level with a single agent, and only 26%
treated to <80 mmHg reached it with monotherapy. HOT taught us
that practitioners can achieve very aggressive goals, but it often takes
multiple drugs to reach those goals. Doctors given goals can achieve
them. Although HOT did not clearly discover a DBP level that was
too low, it did show that the subjects treated aggressively did not have
more adverse reactions. If anything, the group randomized to and treated
to <80 mmHg had an improvement in quality of life and cognitive
function, especially when compared with those that were resistant to
therapy (27).
A more recently published trial, the United Kingdom Prospective
Diabetes Study (UKPDS) (28), confirmed the substantial benefit of more
aggressive compared with less aggressive antihypertensive therapy in
type 2 diabetics. In UKPDS, the goal and achieved BP in the control
group were both much higher than in HOT, but the same level of
comparative benefit was achieved.
