August 18th, 2014
New Analysis of Old Study Fuels Debate Over Blood Pressure Guidelines
In the last year new guidelines relating to cardiovascular disease have been the subject of intense criticism and debate. The status of the blood pressure guidelines has been particularly contentious, since several different groups have published contradictory guidelines, while several authors of the most prominent group, the Eighth Joint National Committee, published an impassioned dissent from their own published guideline. Many hypertension experts have taken aim at the change in therapeutic target for systolic blood pressure in patients age 60 or older, from 140 mm Hg to 150 mm Hg.
In an attempt to determine the optimal blood pressure for patients age 60 or older, Sripal Bangalore and colleagues performed a post-hoc analysis of 8,354 patients who participated in the INVEST trial, who were age 60 or older, and who had a baseline systolic blood pressure greater than 150 mm Hg. They divided these patients into three groups: those who reached blood pressure levels below 140 mm Hg (group 1), those who reached blood pressure levels between 140 and 149 mm Hg (group 2), and those who reached blood pressure levels 150 mm Hg or higher (group 3).
In their paper published in the Journal of the American College of Cardiology, the authors performed several analyses of the data. In their first analysis, which did not attempt to adjust for baseline differences in the three groups, a primary endpoint event (death, nonfatal MI, or nonfatal stroke) occurred in 9.36% of patients in group 1, 12.71% of patients in group 2, and 21.32% of patients in group 3 (p<0.0001).
The investigators then adjusted for multiple differences between the groups. They calculated that when compared to group 1, patients in group 2 did not have a significant increase in the primary endpoint, but they did have significant increases in risk for cardiovascular mortality, total stroke, and nonfatal stroke. Compared to patients in group 1, patients in group 3 had a significant increase in the risk of a primary outcome event, as well as significant increases in risk for all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke.
The authors said their findings re-affirm the more stringent blood pressure target of 140 mm Hg in this population and these results should be used to inform the debate over the new guidelines. This position received an endorsement from the presidents of the American College of Cardiology and the American Heart Association, Patrick O’Gara and Elliott Antman. They released the following statement:
“This study supports the concerns raised by many stakeholders, including the American College of Cardiology, the American Heart Association and a number of the individual members of the ‘JNC 8’ panel (Ann Intern Med. 2014;160(7):499-503.), about the panel’s 2013 recommendations to raise blood pressure targets in older patients. This new research suggests that raising the threshold for treatment of hypertension in patients 60 years of age or older with coronary artery disease may be detrimental to the best interest of patients and the public. It underscores ongoing concerns about adopting the unofficial 2013 targets as proposed by the panel originally appointed to write JNC 8. The ACC and AHA, working with the NHLBI, are in the process of assembling the writing panel that will evaluate evidence from a variety of sources and provide a comprehensive update of the hypertension guideline.”
But this view differs sharply from an accompanying editorial by Alan Gradman.
It is important to recognize that these results cannot be used as evidence against the JNC 8 panel’s selection of 150 mm Hg as the threshold for treatment. All patients in the analyzed cohort entered INVEST with an SBP of >150 mm Hg, and all would have been treated according to the new panel guidelines. Although thresholds for treatment and treatment targets are often thought of as identical, they are not….
In effect, the authors have compared the prognosis of “responders” to “nonresponders,” using the post-randomization variable of achieved on-treatment BP as a measure of response. There is considerable evidence that response to treatment is itself a function of patient characteristics, known or unknown, that may independently influence prognosis.”
Gradman calls for new trials to help resolve these problems, but “in the absence of such data, and given the depth and duration of this controversy, it is clear that there is no right answer.”
Sripal Bangalore sent the following response to the editorial:
The editorial is correct in a largely puristic viewpoint. However, if one were to base guidelines only on RCT evidence all our guidelines would have been only a couple of pages in length. For example, 13.5% of STEMI guideline recommendations are based on RCT data. I am all for RCTs to drive our recommendations, but in the absence of that, we have to take the totality of evidence to make a rational decision.
The evidence for <150 is based on two small RCTs, both of which had serious methodological limitations. One trial was grossly underpowered and the second trial showed interaction such that there was potential benefit for those <75 years (vs. >=75 years) with targets <140 mm Hg. In my viewpoint, this hardly qualifies as ‘robust’ evidence for a target of <150 mm Hg.”
Harlan Krumholz offered the following comment about the controversy:
Unfortunately this study is not designed to test optimal target levels. It may be reflecting adherence rates among the subjects, a characteristic known to affect outcomes even among those were taking placebo. It would be a shame if this article was considered to be strong evidence in the current public dialogue about target levels for blood pressure.”