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Blog: Blood pressure-lowering and the J curve–How low should we go?
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.
Franz H. Messerli
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.