Wednesday, March 2, 2011
Franz H. Messerli, MD
A large body of scientific evidence proves that
uncontrolled hypertension increases CV morbidity and mortality. Likewise,
abundant clinical trial data have confirmed that lowering elevated BP decreases
morbidity and mortality.
However, we have to consider that a BP of 0 mm Hg is
associated with 100% mortality. This means, very simply, that the relationship
between on-treatment BP level and the risk for cardiac morbidity and mortality
has to follow a J-shaped or U-shaped curve. The question clinicians are facing
is this: At what BP level does the J curve become clinically significant? Given
that one in four American adults have hypertension and only one-third of this
population has their high BP under control, the question as to the physiologic
range of this J curve is clinically important.
In 1991, Farnett and colleagues reviewed 13 studies that
stratified CV outcome by level of achieved BP in 48,473 treated hypertensive
patients with at least 1 year of follow-up. They found no consistent J-shaped
relationship between treated BP and stroke, but there was a consistent J-shaped
relationship for cardiac events and diastolic BP. The nadir was 85 mm Hg; lower
diastolic BP levels were associated with increased risk for cardiac events.
This makes sense because coronary arteries are perfused during diastole only;
thus, a J curve should be most apparent for diastolic pressure and coronary
events.
Notably, some studies denied the existence of a J-shaped
curve in their results, including the Hypertension Optimal Treatment Study
(HOT) and the Cardiovascular Health Study (CHS). However, when the HOT data
were re-analyzed 2 years later, Cruickshank and colleagues said although there
was no J curve for nonischemic patients, there was a pronounced J curve in the
data for the ischemic patients in the HOT study.
Similarly, in the CHS, there was a clear J-shaped curve
between diastolic BP levels and the risk for coronary artery disease. This is
very similar to the Barnett data.
The INVEST trial
In a re-analysis, the INVEST team examined the
relationship between systolic and diastolic BP and the risk for adverse
clinical outcomes. Both primary and secondary outcomes were related to systolic
and diastolic pressures in a J-shaped pattern with a nadir at 119/84 mm Hg. The
J curve was fairly flat for systolic pressure, but quite steep for diastolic
pressure and risk for primary outcome, with a leveling off at the nadir and
then an exponential increase in MI at about 70 mm Hg. The findings were based
on 2,239 patients who achieved a diastolic BP of 61 to 70 mm Hg and 176
patients with a diastolic of 60 mm Hg or lower. Specifically, risk doubled for
the primary endpoint at between 60 and 70 mm Hg and tripled with a diastolic
pressure of less than 60 mm Hg. Interestingly, the J curve was pronounced for
diastolic BP and risk for fatal and nonfatal MI, but for fatal/nonfatal stroke,
the J curve was shallow and the minimal increase in risk beyond the nadir did
not reach statistical significance.
Covariate analysis of INVEST detected three significant
interactions with diastolic BP and the primary outcome: hypocholesterolemia
(P=.0001), prior revascularization (P=.005) and diabetes
(P=.002). Patients with hypercholesterolemia or diabetes and low
diastolic pressure had more events. By contrast, revascularization appeared to
confer some protection against events with lower BP; that is, patients who have
undergone revascularization appear to tolerate a lower diastolic pressure
better. Importantly, neither BMI nor diagnosis of cancer interacted with the
diastolic J curve.
Re-evaluating other studies
Ever since the INVEST data were published, several other
sets of data were re-analyzed. Thus, a J-shaped curve between on treatment BP
and outcome was documented in the Syst Eur, ACTION, TNT, ONTARGET, VALUE and
PROVE-IT studies. As expected, in most of these studies, the J curve was more
pronounced between on treatment diastolic pressure and CAD than between BP
(systolic or diastolic) and stroke or other outcome. Thus, the J curve is alive
and well. However, this does not mean that the only explanation for this
phenomenon is compromise of coronary flow because of too low a diastolic
pressure. Conceivably, so-called reverse causation could be a pathophysiologic
factor as well: Patients have low BP because of concomitant extra cardiac
morbidity and are therefore at a higher risk of dying. Also, coexistence of
vascular disease increasing pulse pressure could partially explain the
phenomenon of a J curve.
Of interest, however, is that in some of the recent
studies, of which ACCORD is a classic example, aggressive BP-lowering seems to
have no significant effect. At the end of almost 5 years’ follow-up,
targeting systolic BP <120 mm Hg as compared with <140 mm Hg did not
reduce the rate of a composite outcome of fatal or non-fatal major CV events.
However, not surprisingly, intensive BP therapy reduced the risk for stroke vs.
standard therapy. To my way of thinking, a plausible explanation of this target
organ heterogeneity is very simply that the heart is more susceptible to lower
diastolic pressure than is the brain.
Conclusions
In summary, the J-curve issue remains controversial.
What is clear is that diastolic pressure can be lowered too much with
antihypertensive therapy — particularly in patients with clinically
significant coronary disease. Too low a diastolic pressure increases the risk
for myocardial ischemia and MI. The good news is that systolic BP can be
lowered into the 110 mm Hg range without having a negative effect on target
organs. Hence, practicing physicians may find themselves in the uncomfortable
position that one organ (ie, the heart or the brain) is requiring a BP that the
other organ (ie, the heart) cannot afford. How to therapeutically deal with
this issue has not been resolved.
For more information:
- Farnett L. JAMA. 1991;265:489-495.
- Pepine C. JAMA. 2003;290:2805-2816.
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