Subgroup Analysis From ACCORD BP Prompts More Debate on Hypertension Targets

May 07, 2010

May 7, 2010 (Updated October 1, 2010) (New York, New York) Delving deeper into the findings of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP study reveals that certain subgroups may benefit more from intensive BP lowering because they are at higher absolute risk of stroke. Among these are the elderly, African Americans, and those with prior cardiovascular disease, said Dr William C Cushman (Veterans Affairs Medical Center, Memphis, TN), who presented the new data at a late-breaking clinical-trials session at the American Society of Hypertension (ASH) 2010 Scientific Meeting.

Dr William C Cushman

Although these subgroups did not experience any greater reduction in stroke than that seen overall in the ACCORD BP trial, "due to their higher absolute risk, these subgroups would be expected to derive greater benefit from treatment to lower BP goals," said Cushman. Nevertheless, he stopped short of recommending that these groups be targeted for more intensive BP lowering, stating that more analyses were needed.

The results of the ACCORD BP study overall, presented earlier this year at the ACC meeting, also by Cushman, showed that there was no difference in the primary end point--a composite of cardiovascular events--between those diabetics in whom systolic blood pressure was intensively lowered to <120 mm Hg and those who received standard therapy to achieve BPs of <140 mm Hg. At the time, Cushman said it was probably reasonable to forget all about the 130-mm-Hg BP goal in diabetics, with the evidence suggesting that 140 mm Hg was an appropriate target in these patients; ACCORD BP was widely interpreted as a negative trial.

Dr Henry Black

But session chair Dr Henry Black (New York University Center for the Prevention of Cardiovascular Disease, NY) said: "This doesn't sound like the interpretation I saw in the press" back then.

Others in the audience concurred. Dr Samuel J Mann (Weil Cornell Medical Center, New York, NY) told heartwire : "To conclude that this study was a negative study, I disagree. There was a definite reduction in events, [the intensive therapy] cut stroke by almost half, and once you go out beyond five years and the numbers it prevents get bigger and bigger, it's a real reduction." Dr Clive Rosendorff (Mount Sinai School of Medicine, New York, NY) added: "I think it's really a positive trial, because there was an improvement in stroke outcomes and perhaps more important, there was no harm done."

Cushman remains noncommittal, however. "The primary outcome of ACCORD BP was not reduced [with the intensive-treatment arm], and the secondary outcome, stroke [although it was significantly reduced, by 41%], was not real common . . . so I'm not sure we can recommend a goal of <120 mm Hg in all diabetics." Further regression analyses is needed to "hopefully more clearly define whether we can tell, 'here's the population that is at risk,' and decide whether we should treat more aggressively," Cushman said.

Further Trials Should Be Entertained; JNC 8 Will Consider All Findings

But Cushman does believe that further trials looking at intensively lowering BP "should be entertained." This is because adverse effects--which were more common in the intensive-treatment arm in ACCORD BP--"were mostly reversible and associated with something else going on," and the new subgroup analysis found no evidence of any J-curve effect in those with very low initial diastolic pressures (<72 mm Hg), which is reassuring, he noted.

Dr Franz Messerli

One such study is under way, he noted: the Systolic Blood Pressure Intervention Trial (SPRINT) is comparing a strategy of lowering systolic BP to <120 mm Hg vs <140 mm Hg in patients 55 years or older with hypertension (defined as systolic BP >140 mm Hg) or prehypertension and stage 3 chronic kidney disease who also have one or more additional CVD risk factors.  The primary outcome will be a composite of CV outcome and progression of kidney disease. 

"Ultimately, guidelines will have to include ACCORD BP and all the data and make a decision about the BP recommendation for diabetes," Cushman said. "JNC 8 will look at the totality of evidence; I'm not going to hazard a guess at what might be said there."

The new JNC 8 guidelines on hypertension, which will include recommendations for diabetics, are eagerly awaited, but their release keeps being postponed.

Dr Eduardo Ortiz (National Heart, Lung, and Blood Institute, Bethesda, MD) who also spoke at the ASH meeting, says they are now expected to be published in 2011.

[The JNC 8 delay is] unbelievable; it's like Moses being in the desert for years and years.

However, many physicians are becoming increasingly exasperated by the constant delays and pushing back of the timetable for these guidelines.

Black told Ortiz: "We are waiting; I hope we have something worth waiting for." And Dr Franz Messerli (St Luke Roosevelt Hospital, New York, NY) commented to heartwire : "It's unbelievable; it's like Moses being in the desert for years and years."

Updated Guidelines on Hypertension in Blacks Shoot for <130 mm Hg

In the midst of all this debate, one group of doctors has felt able to make new recommendations--those representing the International Society on Hypertension in Blacks (ISHIB). Dr John M Flack (Wayne State University, Detroit, MI) presented an overview of the updated ISHIB guidelines--soon to be published in a hypertension journal--at the ASH meeting.

Dr John M Flack

ISHIB has, somewhat controversially, in view of the ACCORD BP data, gone for target BP levels in African Americans of <135/80 mm Hg in primary prevention and <130/80 mm Hg in secondary prevention, and these are viewed not as floors "but as ceilings," said Flack, indicating that ISHIB would be happy with blood pressures that are even lower than these targets.

Flack told heartwire : "The thing that really swayed us with ACCORD BP was that the prespecified secondary end point, stroke, was strikingly reduced, by almost 50%; we're dealing with a population where stroke rates are two- to threefold higher than the white population, so we felt that was highly relevant to our population." And other studies have shown reductions in retinopathy and proteinuria when systolic pressures are lowered to below 130 mm Hg, he said.

I'm still going to target trying to get them significantly under 130/80 mm Hg. . . . this thing about the J-curve has been way overblown.

"So when we take all those together: stroke, as well as progressive retinopathy and nephropathy--microvascular complications that are rampant in the black population--there is no way we can ignore these, when, for example, the patients we take care of are going blind at an inordinately high rate, and we know BP control is actually more important for preventing that than glycemic control."

Dr Suzanne Oparil

In fact, says Flack, "in any patient I take care of, regardless of ethnicity, I'm still going to target trying to get them significantly under 130/80 mm Hg; in properly conducted trials, this thing about the J-curve has been way overblown. I think the J-curve is something that the experts spend a lot of time on, and the real problem is not a J-curve--there's no credible evidence there's a treatment-induced J-curve."

Flack says the only patients in whom he would worry somewhat about lowering BP too much are those with only coronary disease and stiffer vessels, often the very elderly.

But Dr Suzanne Oparil (University of Alabama, Birmingham) who is on the JNC 8 committee, asked by heartwire to give her view on the new ISHIB guidelines, said: "I don't know how they got their evidence."

Targeted, Individualized, Therapy Will Be the Key

Dr Giuseppe Mancia

Debate on this subject will undoubtedly continue for many months and years, even after JNC 8 is published. Dr Giuseppe Mancia (University of Milan Bicocca, Monza, Italy), who headed the committee that reappraised the European hypertension guidelines last year--before ACCORD BP was reported--wondered at the ASH meeting: "Are we going to have a turnaround, so that rather than being more aggressive in high-risk individuals, we should be more careful in these patients?"

The answer is that it depends on the patient, he said, stressing that the best approach is tailored therapy, targeted to the individual.

Aggressive BP lowering should still be the preferred strategy when the risk of stroke prevails.

"Aggressive BP lowering should still be the preferred strategy when the risk of stroke prevails," he said. Others polled by heartwire agreed, predicting that different goals for different patient populations would be the most likely recommendations to come out of JNC 8.

"What I think we should avoid is that guidelines are set in stone as being the ultimate, irrevocable way in which to deal with patients, because there is always the individual patient who has unique issues," Rosendorff commented.

And Mann says he believes guidelines "are helpful to people who are not in this specialty; for people in the specialty, we are going to do what we think is right. Guidelines are nice, but they don't handle the issue of individualization well."

Why are all of those patients out there above 140 mm Hg still walking around, undertreated and still hypertensive? That's the real issue.

And ultimately, says Rosendorff, "The real day-to-day problem in hypertension is not whether you should lower the [systolic] BP to below 140 mm Hg or below 120 mm Hg, but why are all of those patients out there above 140 mm Hg still walking around, undertreated and still hypertensive? That's the real issue."

TNT/CARDS Analysis: BP Predicts Stroke, LDL Predicts Cardiac Events

Dr Prakash Deedwania

A separate, late-breaking presentation on pooled data from the TNT and CARDS studies, presented by Dr Prakash Deedwania (University of California, San Francisco School of Medicine) at the ASH meeting, showed that high baseline systolic BP was a significant risk factor for stroke, but not for cardiac events, in the more than 12 000 patients included in these two studies. Conversely, baseline LDL cholesterol was predictive of cardiac events, but not of stroke.

Systolic BP and LDL had significant predictive relationships with outcomes, said Deedwania, "but their effects appear to be different on the cerebrovascular and coronary systems."

Rosendorff said although this finding has been suspected: "I don't think it's been quite as clearly stated as this. The data are very compelling. We heard that there is a clear difference between the effects of lowering BP and lowering LDL cholesterol on stroke vs coronary events; BP lowering protects against stroke events, and LDL lowering protects against coronary events."

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