Return of the J-Curve: TNT Analysis Shows That BP Can Be Too Low in CAD Patients

May 08, 2009

May 8, 2009 (San Francisco, California) — An analysis of one of the major "lower-is-better" cholesterol trials has shown that lower might not be best when it comes to blood pressure. In fact, in this group of patients with coronary artery disease, despite substantial lowering of LDL-cholesterol levels, a J-curve relationship exists between systolic and diastolic blood pressure and cardiovascular events.

"It stands to reason that when you lower blood pressure too much, you can do harm," said study investigator Dr Franz Messerli (St Luke's-Roosevelt Hospital, New York). "After all, if blood pressure is zero, mortality is 100%. So somewhere there must be a nadir, below which the lowering of blood pressure becomes counterproductive."

The findings, from an analysis of the Treating to New Targets (TNT) study, were presented here yesterday at the American Society of Hypertension 2009 Scientific Meeting in San Francisco, CA.

Paradoxical Increase in Risk With Lower Blood Pressures

The existence of the so-called J curve--a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure--has been argued about for years, and Messerli has been a proponent of the phenomenon. As reported previously by heartwire, Messerli and colleagues published an analysis of the INVEST study, a trial comparing two antihypertensive regimens in 22 576 patients with hypertension and coronary artery disease, and found that excessively lowering diastolic blood pressure was harmful.

After all, if blood pressure is zero, mortality is 100%. So somewhere there must be a nadir at which the lowering of blood pressure becomes counterproductive.

In this analysis, however, the investigators wanted to determine whether the J-curve relationship existed between blood pressure and cardiovascular events among patients undergoing aggressive management of other cardiovascular risk factors. In TNT, men and women aged 35 to 75 years with clinically evident coronary artery disease and LDL-cholesterol levels <130 mg/dL were randomized to conventional treatment with atorvastatin 10 mg or aggressive therapy with the 80-mg dose.

Like INVEST, the relationship between systolic and diastolic blood pressure and the incidence of major cardiovascular events--the primary end point consisting of coronary death, nonfatal MI, resuscitated cardiac arrest, or stroke--followed a J-shaped curve. Compared with the reference blood pressures, systolic >130 to 140 mm Hg and diastolic >70 to 80 mm Hg, patients with systolic blood pressure <110 mm Hg had a threefold increased risk of cardiovascular events, whereas those with diastolic blood pressure <60 mm Hg had a 3.3-fold increased risk of events.

Speaking with the media, Messerli said that the nadir--the lowest point of inflection on the morbidity and mortality curves--was 140.6 mm Hg for systolic blood pressure and 79.8 mm Hg for diastolic blood pressure, which is higher than the nadir observed in INVEST. In that study, the lowest point on the J curve was approximately 112/72 mm Hg.

"The good news is that it is a relatively shallow curve," said Messerli. "You can lower blood pressure considerably more before you actually see a drastic increase in the primary end point. But when you go to a diastolic pressure below 60 mm Hg, there is a fourfold increase in the primary end point."

Why the Paradox, Doc?

Explaining the paradox that lower blood pressures might adversely affect cardiovascular morbidity and mortality, Messerli said that it's possible that low blood pressure leads to an underperfusion of the coronary arteries during diastole, which in turn increases the risk of MI. Also, low diastolic blood pressure results in high pulse pressures, which leads to endothelial dysfunction, stiff arteries, and vascular disease. It is also possible there is "reverse causation" at play, he noted, in that patients with low blood pressure might actually be sicker patients.

Discussing the concept that blood pressures that are too low might not be good, press conference moderator Dr William White (University of Connecticut Health Center, Farmington) noted that the patients in TNT, as well as INVEST, all had coronary artery disease and wondered whether the same relationship exists between those without evidence of coronary disease. Messerli said the relationship is likely still there, but to a much lesser extent.

"Most of us would agree that at least with coronary artery disease and diastolic pressure you have to be a bit careful," he said. "If the patient is post-MI and diastolic blood pressure is around 60 mm Hg, that's not exactly what we would like to see."

White agreed, saying that in patients with diastolic levels this low, he would lower drug dosages to raise diastolic blood pressure 10 or 12 mm Hg and still feel comfortable that they were protected from cardiovascular events but without the risk of underperfusion.

"Once we scare physicians by saying, hold on, you could go too low, they are less aggressive in controlling blood pressure," cautioned Messerli.

Pfizer sponsored the TNT study.

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