INVEST: Mortality Hazard With Lowest Blood Pressures in Diabetics With CAD?

March 14, 2010

March 14, 2010 (Atlanta, Georgia) — Intensive blood-pressure control in patients with diabetes and cardiovascular disease was associated with a higher mortality rate than usual control, in a new retrospective analysis of the International Verapamil SR-Trandolapril (INVEST) trial.

Dr Rhonda Cooper-DeHoff

The analysis, presented today at the American College of Cardiology (ACC) 2010 Scientific Sessions, found that patients whose systolic blood pressure was lowered to 130 to 140 mm Hg had a better outcome than those with systolic pressures over 140 mm Hg. But those whose systolic blood pressure was reduced to below 130 mm Hg did not appear to receive any additional benefit and had a higher mortality rate.

Dr Rhonda Cooper-DeHoff (University of Florida, Gainesville), who presented the study, commented to heartwire : "The most important message from our analysis is that it is still critically important to lower systolic blood pressure to below 140 mm Hg in diabetes patients with heart disease. But after this study, I would say that it is not beneficial and could be harmful to use more aggressive treatment to get down to values below 130 mm Hg."

In Line With ACCORD

These results are in line with those from the blood-pressure arm of the ACCORD trial, also released today, showing no benefit (but also no harm) of tighter blood-pressure control in diabetic patients, although the tight-control group in ACCORD had a lower blood-pressure target--120 mm Hg. "The two trials had slightly different populations. While both involved diabetic patients, in INVEST all patients also had coronary heart disease, whereas in ACCORD only around 30% had heart disease, but the results give a similar message--that we should not be aiming to lower systolic pressure below 130 mm Hg in these patients," Cooper-DeHoff commented. "Instead, we should be turning our attention to other advice for these patients, like concentrating on better diet and lifestyle."

Change to the Guidelines?

Dr William Cushman

ACCORD investigator Dr William Cushman (VA Medical Center, Memphis, TN) agreed with Cooper-DeHoff's stance. He explained to heartwire that current US guidelines (JNC-7) recommend a systolic blood-pressure target of below 130 mm Hg for diabetic patients, but this been based on epidemiology rather than outcome studies. "Our results and those of INVEST do not support this recommendation. The guidelines committees will have to assess all this and decide what to do. I can't say what JNC-8 will say, but my personal opinion is that a target of less than 140 mm Hg is reasonable, and we should not keep giving extra drugs to get patients down to levels below 120 to 130 mm Hg. It takes a lot of effort to get patients down to 120 or below, often with three or more antihypertensive drugs, so I would say that we now don't need to be doing this, and for most patients no more than two drugs should be adequate."

Is the Mortality Increase Meaningful?

But experts warned against attaching too much significance to the increased mortality signal seen in the INVEST analysis. One of the panelists at the ACC late-breaking trial session at which INVEST was presented noted that patients who were uncontrolled (BP>140 mm Hg) were on more antihypertensive drugs than those who were controlled. "So these results may not be broadly applicable. It may be a heterogeneous effect. For example, there may be patients with triple-vessel disease who cannot tolerate a blood pressure below 120, but then others with single-vessel disease may be fine with a pressure as low as 110." Others offered a reminder that INVEST was a retrospective analysis and its results should therefore be interpreted with some caution.

Cushman was also cautious about reading too much into the higher mortality finding in INVEST. He commented to heartwire : "Anytime we've done a randomized trial of a lower blood pressure vs a higher blood pressure, we've never shown detriment for the lower-pressure group. We've often not shown benefit, as in ACCORD, so what you have in INVEST is what's often seen in retrospective studies. It doesn't mean you ignore it, but basically what it says is that if your goal is 140 and you get down to 100, then there's something wrong with that patient. That being said, in the absence of benefit for going to lower goals, even if it's 130 and certainly 120, then at least there's that theoretical possibility of increased risk. But I think most of the trials retrospectively looking at on-treatment blood pressures are just finding a high-risk population that happens to get really low pressure when you put them on a little bit of drug."

INVEST Details

For the study, INVEST randomly assigned 6400 patients with diabetes and CAD to two blood-pressure lowering strategies starting with verapamil SR (Isoptin, Abbott Laboratories) or atenolol, with both groups adding in trandolapril (Mavik, Abbott Laboratories) and hydrochlorothiazide. The target was a blood pressure of less than 130/85 mm Hg. The main results, presented previously, showed no difference in cardiac outcomes between the two approaches.

For the current analysis, patients were categorized according to the degree of blood-pressure control actually achieved. Patients with a systolic blood pressure of 140 mm Hg or higher were classified as "not controlled." Those with a systolic blood pressure below 130 mm Hg were classified as "tight control" and those with a systolic blood pressure between 130 and 140 mm Hg were classified as "usual control."

Results showed that during the follow-up period, patients in the uncontrolled group had nearly a 50% higher combined risk of death/MI/stroke when compared with the usual-control group. Those in the tight-control group had a similar risk to those in the usual-control group in terms of the combined end point; however, further analysis showed an increase in the risk of all-cause death in the tight-control group when compared with the usual-control group. This increase became apparent about 30 months into the study and persisted for an additional five years of follow-up.

INVEST: Outcome Results

Outcome Tight control (n=2255), % Usual control (n=1970), % Not controlled (n=2175), % p
Death/MI/stroke* 12.7 12.6 19.8 < 0.0001
Nonfatal MI 1.3 1.7 3.1 0.008
Nonfatal stroke 1.0 1.3 2.4 0.001
All-cause mortality 11.0 10.2 15.4 < 0.0001

*Primary outcomez

When researchers then analyzed blood pressure in 5-mm-Hg-increment reductions in the tight-control group, they discovered that the increase in mortality became apparent only at a systolic blood pressure of 115 mm Hg and increased further as blood pressure was lowered beyond this level.

Lightening the Physician's Load

Cushman commented to heartwire : "We saw no harm in our 120-mm-Hg group in ACCORD, and in the INVEST subgroup analysis, harm was not seen until pressures went below 115 mm Hg. This fits in with other studies, such as SAND, which had a goal of 115 mm Hg and showed no harm, so I don't think we need to panic, but neither should we put in the effort required to get patients down to these lower pressures. However, if patients are on ACE inhibitors or other antihypertensive agents for other reasons, such as for heart failure, and their blood pressure is below 130, I would say this is fine. I would just not push patients down just for the blood-pressure reduction."

Cooper-DeHoff agreed that these results should lighten the load of the physician. "The target of 130 to 140 mm Hg is much easier to attain. Typically in the community, only around 20% to 30% of diabetics would achieve a systolic pressure below 130 mm Hg. But 50% to 60% would be in the 130–140-mm-Hg range."

Moderator of the ACC press conference at which these trials were presented, Dr Doug Weaver (Henry Ford Health System, Detroit, MI), said: "I was surprised by these findings. I would expect lowering blood pressure to be very beneficial. I guess the new message is: 'Good blood-pressure control is desirable, but perfect control is not so good for these patients.' "

Some other commentators said doctors should be cautious in extrapolating these results to all patients. Dr Henry Ginsberg (Columbia University, New York), another ACCORD investigator, pointed out: "We do these clinical trials in very sick patients. The results are not necessarily applicable to younger diabetic patients who do not have CAD."

Abbott Laboratories provided funding for INVEST.

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