Our examination of the independent effects of diastolic and systolic blood pressure on mortality confirms a central tenet of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7): systolic blood pressure elevations are more important than diastolic blood pressure elevations in persons over age 50. In fact, in our data, diastolic blood pressures are largely irrelevant in this age group. The situation was reversed in persons age 50 and younger: in whom diastolic blood pressure was the more important predictor of mortality.
Our analysis was also directed at a broader question that we hope JNC 8 will consider in its ongoing deliberations: What is the impact of various definitions of normal blood pressure? The current definition of normal is less than 120/80. Our analysis offers one possible alternative definition: a blood pressure that does not confer an increased mortality risk in a cohort of over 10,000 individuals followed for nearly 20 years. From our data this would mean that abnormal for individuals over age 50 would be a SBP of ≥140 (independent of DBP), and for individuals less than 50, a DBP
≥100 or a SBP
≥200. While it should not be viewed as the final word on this topic, we hope it serves as an example of an alternative approach. If nothing else, our findings highlight that the choice about the approach used to define normal blood pressure will impact literally millions of Americans.
Our analysis has a number of limitations. The most obvious is that we have no data about treatment. It is possible that subsequent treatment might attenuate the relationship between elevated blood pressure and mortality. Given this concern, we sought the oldest data possible—when blood pressure treatment was less widespread. And within our data there is evidence that suggests treatment explains little of what we observed.
Because patients were enrolled in the early 1970s, any treatment that occurred would have been directed at elevations in diastolic blood pressure. Nevertheless our analysis of the effect of diastolic blood pressure (without adjustment for systolic blood pressure) shows a strong dose-response relationship. Were higher diastolic blood pressures more likely to have been successfully treated, one would have expected this relationship to be much flatter. Furthermore, we performed an additional analysis focusing on the best available proxy for the absence of treatment: that of having little income. When we restricted our analysis to those with family incomes of less than $10,000 per year (approximately $50,000 or less in today's dollars), we identified exactly the same blood pressure categories as being associated with significant increases in mortality.
Our findings do not include reductions in quality of life due to cardiovascular morbidity not directly associated with a decrease in years of life. The exact magnitude or proportion is not well known, nor is the corresponding impact this would have on treatment decision making (i.e., the decision to treat a patient to reduce cardiovascular complications even if there was no reduction in mortality). Practically speaking, however, it is important to point out that all-cause mortality and cardiovascular mortality are highly correlated—a finding confirmed in data from over 300,000 men enrolled in the Multiple Risk Factor Intervention Trial (MRFIT).14
Furthermore, the largest meta-analysis of 1 million adults from 61 prospective observational studies also found that non-vascular causes of death were positively related to blood pressure.15
Given that our data are based on exceptionally long-term follow-up, that approximately one-third of individuals died, including almost two-thirds of those over age 50, and the known close association of cardiovascular events with all-cause mortality, we believe that clinically meaningful cardiovascular morbidity (and the corresponding decrement in quality of life) and mortality should have been largely captured in our measurement of all-cause mortality.
Furthermore, we believe there is a strong theoretical argument for using all-cause mortality as the primary outcome. First, it is the least ambiguous outcome measure. Because the fact of death can be unambiguously ascertained, it is the outcome least subject to measurement bias. Second, all-cause mortality is the most comprehensive measure of the mortality impact of a condition. Because it is comprehensive, it avoids having to assume no relationship between one form of death and another—and thus avoids the potential problem of either underestimating risk (e.g., failing to recognize that elevated blood pressure might be associated with non-cardiovascular deaths) or overestimating it (e.g., failing to recognize that there might be a trade-off between cardiovascular deaths and non-cardiovascular deaths).16
Because they are based on one dataset, our findings by themselves are insufficient to develop policy. We would hope others would reconsider the question of what constitutes normal blood pressure using other datasets. We also recognize that our approach for defining normal adds an additional complexity to the current approach because it is modified by age (SBP less than 140 for those over age 50 and a blood pressure under 200/100 for those age 50 and younger). But even a small simple expansion in the definition of normal—from under 120/80 to under 140/90—would have a tremendous impact: affecting about 80 million Americans.
The current approach to define normal as less than 120/80 is presumably based on detectable increases in risk above that level. But there are always bound to be small, detectable effects if we study enough people. And the threshold to label individuals as “abnormal” ought to require more than simply any detectable effect, in any outcome, in any size sample.
The reason is because there are costs associated with labeling people as abnormal. There are human costs: both for the people who have been turned into patients (and who have been informed that they are now more vulnerable to disease) and for the clinicians who are increasingly overwhelmed by the number of diagnoses they face (arguably distracting them from the patients who need them most). There are also the tremendous logistical and financial costs associated with millions of new diagnoses—a cost that may be even larger in this country to the extent it impedes progress toward universal access.
Finally, there is the problem of excessive treatment. Regardless of what is recommended, the tendency of clinicians will increasingly be to treat lower blood pressures to make them “normal.” When abnormal is defined to include values in which the risk itself is ambiguous, the ability of treatment to change that risk becomes even less certain. In the absence of randomized trials demonstrating the benefit of intervening in this grey area, we urge caution in suggesting that individuals are abnormal (and, in doing so, inadvertently encouraging more intervention). But the most important concern may be the potential for harm. Careful readers have likely already noted the increased mortality associated with very low blood pressures in those over age 50. Much of this effect undoubtedly reflects individuals with low blood pressure because of underlying cardiovascular disease or poor health status. However, given the recent finding that increased all-cause mortality may be higher with tight blood pressure control in hypertensive patients with diabetes,17
it may also reflect the risk some individuals may face if they are excessively treated. The finding of increased mortality following intensive glucose lowering18
is another example that refutes the previously held notion that achieving lower (whether it is glucose levels or blood pressure measurements) will necessarily improve mortality and should, at least, encourage clinicians to consider the possibility that intensive blood pressure lowering may not be helpful or necessary, and in fact could be hazardous for patients in general. The potential harm would seem to be greatest in patients whose baseline blood pressure is near normal.
At some point, it becomes incumbent on consensus panels (like JNC 8) to consider these trade-offs in their definition of normal. The fundamental question is how much of an effect is worth worrying the population about and experiencing the associated costs? To do this, they may well need to consider unfamiliar questions, such as: If we cannot reliably see a mortality effect in a large group of individuals followed for nearly 20 years, should we define the condition as abnormal? We believe considering this kind of approach represents a critical step in ensuring that diagnoses are given only to those with a meaningful elevation in risk and that interventions are targeted towards individuals most likely to benefit.