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CLARIFY: Low BP linked with adverse CV outcomes in high-risk patients
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In patients with stable CAD, BP below 120 mm Hg systolic or 70 mm Hg diastolic was associated with elevated risk for CV death, MI and stroke, according to findings from the CLARIFY registry.
“Some argue ‘the lower, the better’, but there is a concern that patients with [CAD] may have insufficient blood flow to the heart if their [BP] is too low,” Philippe Gabriel Steg, MD, from the cardiology and physiology departments, Départment Hospitalo-Universitaire FIRE, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris Diderot University, Sorbonne Paris Cité, France, said in a press release.
Steg and colleagues analyzed data from 22,672 patients (mean age, 65 years; 75% men) with stable CAD from 45 countries who were treated for hypertension between November 2009 and June 2010.
Philippe Gabriel Steg
The primary outcome was a composite of CV death, MI or stroke. Secondary outcomes included each component of the primary outcome, all-cause death and hospitalization for HF. Median follow-up was 5 years.
Patients were stratified by systolic and diastolic BP levels of 10 mm Hg increments, with 120-129 mm Hg systolic BP and 70-79 mm Hg diastolic BP serving as the reference groups.
Systolic BP > 140 mm Hg (adjusted HR = 1.51; 95% CI, 1.32-1.73) and diastolic BP > 80 mm Hg (adjusted HR = 1.41; 95% CI, 1.27-1.57) were each associated with increased risk for the primary outcome at the end of the study period.
However, systolic BP < 120 mm Hg (adjusted HR = 1.56; 95% CI, 1.36-1.81) and diastolic BP < 70 mm Hg (adjusted HR = 1.41; 95% CI, 1.24-1.61) were also associated with increased risk for the primary outcome, with a larger risk seen in those with diastolic BP < 60 mm Hg (adjusted HR = 2.01; 95% CI, 1.5-2.7).
“Our observations are in agreement with the fact that after decades of hypertension trials, the benefit of lowering [BP] to less than 140 mm Hg remains unquestionable, whereas the benefit of lowering [BP] to less than 130 mm Hg is uncertain,” the researchers wrote in The Lancet.
Steg, a member of the Cardiology Today’s Intervention Editorial Board, said in the release that “the findings support the existence of a J-curve phenomenon, where the initial lowering of BP is beneficial but further lowering is harmful.” – by James Clark
References:
Steg PG, et al. Registries miscellaneous. Presented at: European Society of Cardiology Congress; Aug. 27-31, 2016; Rome.
Vidal-Petiot E, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)31326-5.
Disclosures: The registry was funded by Servier. Steg reports financial ties with Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Medtronic, Merck, Novartis, Pfizer, Regeneron, Roche, Servier and The Medicines Company.
Perspective
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Michael A. Weber, MD
In some respects, this new study has supported the findings of SPRINT, although not entirely. The important thing to remember about SPRINT is that even though a lot of publicity was given to the benefits of achieving a systolic BP below 120 mm Hg, in fact, this SPRINT-measured BP is not really relevant to everyday clinical practice. BP in SPRINT was measured in a very special way using completely automated equipment while the patient remained unobserved by health care personnel. This was done to minimize the “white-coat effect,” but this method results in BPs 7 mm Hg to 10 mm Hg lower than we would normally obtain with a carefully measured office BP. The SPRINT researchers reported that their intensively treated patients finished with a mean systolic BP of 121 mm Hg, but in reality, this corresponds to an office BP of roughly 130 mm Hg, which is consistent with the findings of CLARIFY. To that extent, CLARIFY is confirmatory of SPRINT.
The patient population in CLARIFY was different from SPRINT in that 100% of the patients in CLARIFY had some evidence for CAD, whereas in SPRINT, CAD was an inclusion criterion but wasn’t the only one. For instance, in SPRINT there were patients enrolled on the basis of a high Framingham CV Risk Score or simply because they were aged 75 years or older.
What SPRINT did not address is what would happen at a SPRINT-measured systolic BP of 110 mm Hg, which corresponds to roughly 120 mm Hg in CLARIFY. Maybe the SPRINT investigators might have seen a J-curve effect and the beginnings of an increase in CV events at such a low target, just as in CLARIFY. But we don’t know because it wasn’t done.
One critical thing to remember is that the SPRINT study did not include patients with diabetes. Probably patients with diabetes are more at risk more than those without diabetes for a J-curve effect. My colleagues and I reported a study based on the ACCOMPLISH results (Weber MA, et al. Am J Med. 2013;doi:10.1016/j.amjmed.2013.01.007) which showed that, just like in the new CLARIFY study, pushing the systolic BP to < 120 mm Hg significantly benefited stroke but had an adverse effect on MI and coronary events. When we looked at the data more carefully later, we discovered that this J-curve effect was driven entirely by patients with diabetes. We found no evidence of a J-curve in high-risk patients without diabetes. So we need to take a closer look at CLARIFY and ask questions about whether there were important differences between patients with and without diabetes when they were analyzed separately for outcomes at low BPs.
Clinicians should shoot for a systolic BP of 130 mm Hg in their patients with CHD. That is probably a good target for any high-risk patient, including those with history of stroke or vascular disease of any sort.
I think these results will not greatly change where the new American College of Cardiology/American Heart Association guidelines are going to go. I am assuming, based just on SPRINT alone, the guidelines would recommend a target of 130 mm Hg, particularly in high-risk patients. But adding to the complexity of this are the results of HOPE-3, which did not show the same findings as SPRINT. Patients with systolic BP > 140 mm Hg treated to < 140 mm Hg got a CV benefit in HOPE 3, but reducing to < 130 mm Hg or beyond, if anything, seemed to be associated with a worsening outcome. One of the big differences between HOPE-3 and SPRINT is that HOPE-3 excluded patients who had any clinical history of coronary events or other CV outcomes. It was a much lower-risk group. I believe that this new study, CLARIFY, will support SPRINT and ACCOMPLISH and other trials in concluding that a systolic BP target of < 130 mm Hg appears to be a desirable one for patients at high risk, but it may be acceptable to have a target of < 140 mm Hg for patients who are at lesser CV risk.
What I found somewhat difficult with CLARIFY were some of the conclusions regarding diastolic BP, in particular the concern about excessive reductions. We all worry about inappropriately low diastolic BP. However, diastolic BP is very difficult to interpret. If you’ve got a healthy young or middle-aged person with low BP — for instance a measurement of 100 mm Hg systolic/58 mm Hg diastolic — that’s fine. But what if the BP is 160 mm Hg/58 mm Hg? That’s a totally different situation, because the low diastolic BP does not indicate healthy arteries and a good prognosis, but rather the presence of stiff arteries that lack the elasticity to support a higher diastolic BP. So diastolic BP is almost impossible to interpret unless you factor it by the corresponding systolic BP. Unlike systolic BP, you cannot easily analyze diastolic BP as an isolated finding. I’m not sure that the currently available analysis of this new trial allows us to fully understand the role of diastolic BP as a mediator of events.
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