HYVET: BP lowering reduces fatal stroke, all-cause mortality in the elderly

Susan Jeffrey

March 31, 2008

Chicago, IL - Results of a randomized trial show that antihypertensive treatment with a sustained release formulation of the diuretic indapamide, with or without the addition of perindopril, significantly reduced fatal stroke, all-cause mortality, and heart failure in patients 80 years of age and older, although the primary end point, fatal or nonfatal stroke, did not reach statistical significance[1].

The study, called the Hypertension in the Very Elderly Trial (HYVET), was halted in August 2007 on the recommendation of the data and safety monitoring board when it became clear that treatment was associated with reductions in stroke and all-cause mortality. It had been scheduled to be completed in 2009.

The findings are published online March 31, 2008 in the New England Journal of Medicine to coincide with presentation here at the American College of Cardiology 2008 Scientific Sessions.

"Elevated blood pressure is common in persons 80 years of age or older, a group constituting the fastest-growing segment of the general population," Dr N igel S Beckett (Imperial College London, UK) and colleagues conclude in their report.

"HYVET provides unique evidence that hypertension treatment based on indapamide (sustained release), with or without perindopril, in the very elderly, aimed to achieve a target blood pressure of 150/80 mm Hg, is beneficial and associated with reduced risks of death from stroke, death from any cause, and heart failure.

"We feel that HYVET now has shown that it's never too late to start antihypertensive medication, and we have expanded the upper limit where there is now clinical evidence of benefit for the treatment of hypertension," Beckett told attendees here.

Uncertainty about benefits in elderly

Despite the clear overall benefit of blood-pressure lowering in preventing stroke and other vascular events, whether treatment of patients with hypertension over the age of 80 is beneficial is still unclear, the authors write. An earlier meta-analysis[2] looking at this question suggested the 36% reduction in the risk of stroke seen with treatment might be offset by possible adverse events, they write, "given a nearly significant increase, by 14%, in the risk of death from any cause (p=0.05)."

Indeed, results from the pilot phase of HYVET[3] were consistent with the earlier meta-analysis, showing a reduced risk for stroke but a possible increase in death from any cause, "such that for each stroke prevented, there was one death from a cause other than stroke," they write.

"In the main HYVET study, we aimed to resolve persistent areas of clinical uncertainty about the relative benefits and risks of antihypertensive treatment in patients 80 years of age or older," the authors write.

Researchers enrolled 3845 patients 80 years of age and older from Europe, China, Australasia, and Tunisia and randomized them to receive either the diuretic indapamide (sustained release 1.5 mg) or matching placebo. At baseline, patients had a sustained systolic blood pressure of 160 mm Hg or higher. The ACE inhibitor perindopril (2 or 4 mg) or matching placebo could be added as necessary to achieve a target systolic BP of 150/80 mm Hg.

The primary end point was fatal or nonfatal stroke.

At baseline, patients in the treatment and placebo groups were well-matched, with a mean age of 83.6 years and a mean sitting blood pressure of 173.0/90.8 mm Hg. Some 11.6% of patients had a history of cardiovascular disease. At two years, there was a difference of 15.0/6.1 mm Hg in BP measured while sitting between the treatment groups. Target BP at that time point was reached in 19.9% of the placebo patients and in 48.0% of the treatment group, a statistically significant difference.

In an intention-to-treat analysis, the primary end point of fatal or nonfatal stroke was reduced in the active-treatment group by 30%, although this finding did not reach nominal statistical significance. "This is equivalent to 11 strokes (95% CI 0-21) being prevented because 1000 patients were treated for two years or one stroke being prevented because 94 patients were treated for two years," the authors write. Benefits of treatment began to be apparent already by one year, they add.

HYVET primary end point: Fatal or nonfatal stroke events by treatment group

End point Active treatment (n) Placebo (n) Hazard ratio (95% CI) p
Fatal or nonfatal stroke 51 69 0.70 (0.49-1.01) 0.06

Treatment was also associated with a 39% reduction in the rate of death from stroke, a 21% reduction in the rate of death from any cause, a nonsignificant 23% reduction in the rate of death from cardiovascular causes, and a 64% reduction in the rate of heart failure, they note. While the finding relating to stroke reduction was consistent with earlier pilot results, Beckett et al write, "the reduction in death from any cause is a new and unexpected result."

HYVET: Secondary outcomes by treatment group

End point Active treatment (n) Placebo (n) Unadjusted hazard ratio (95% CI) p
Death from stroke 27 42 0.61 (0.38-0.99) 0.046
Death from any cause 196 235 0.79 (0.65-0.95) 0.02
Death from cardiovascular causes 99 121 0.77 (0.60-1.01) 0.06
Any heart failure 22 57 0.36 (0.22-0.58) <0.001

During his presentation, Beckett noted that when they calculated the primary end point in the per-protocol population—a population that was identical to the intention-to-treat population minus 23 patients—the primary end point of fatal or nonfatal stroke did reach statistical significance, with a 34% reduction (p=0.03). Cardiovascular mortality was also significantly reduced in this analysis.

Fewer adverse side effects were seen in the active-treatment group than in the placebo group, with 358 vs 448 events (p=0.001); only three events in the placebo group and two in the active-treatment group were classified by the investigator as having been related to the trial medication. Among patients followed for at least two years, there were no differences between groups relating to changes in serum potassium, uric acid, glucose, or creatinine, they note.

The results support a target blood pressure of 150/80 mm Hg, they conclude, "since that target was reached in nearly 50% of such patients in HYVET after two years. Whether further reduction is beneficial still needs to be established." They will have some insight into this in further analyses planned from HYVET, he said.

During a press conference, Beckett acknowledged that the HYVET patients were healthy elderly and that these results can't be extrapolated to frail elderly in nursing homes and those who are demented, a population that was excluded from this study. The HYVET investigators have data on incident dementia in HYVET and plan to present this analysis at the joint meeting of the European Society of Hypertension and the International Society of Hypertension in Berlin in June of this year.

Stick to the evidence?

In an interview, Beckett said sustained-release indapamide, a thiazide-type diuretic, and perindopril were selected for the study because they are both made by the same company, Servier, which was providing some of the funding for the trial, but also because indapamide was formulated in a lower dose than is the case with other thiazide diuretics that were used, certainly when the trial began.

Would he recommend sticking with this combination? Lower doses of diuretics are not widely available, he pointed out, and the previous studies that had shown a suggestion of increased mortality had used higher doses of diuretics. "Normally I wouldn't say this, but I would think because the formulation allowed for a lower dose, perhaps this combination is one to stick with. We know it works." Perhaps in a comparative study other combinations might be better, he added, "but I can't see any comparative studies coming along in the near future."

In general, he said, the elderly have been left out of clinical guidance on hypertension management, and they hope this will change on the basis of these findings. "The American guidelines don't say a thing, the European and British guidelines say there is uncertainty," he said. "So what we're hoping is that we can remove that uncertainty and that future committees that are writing these guidelines will take that on board and perhaps give a stronger statement in terms of what we should be doing."

Not too late to treat in over-80s

In an editorial accompanying the paper, Dr John B Kostis (Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ) points out that the lack of definitive data on the advisability of treating hypertension in people who are 80 years of age or older is reflected in US and European guidelines.

"HYVET puts the question of the usefulness of treating hypertension in the very old to rest and provides important guidance to physicians and the writers of such guidelines," Kostis writes. "A significant and clinically important decrease in the rates of death from any cause and of fatal or nonfatal heart failure was found at a median of 1.8 years of follow-up."

Although in the intention-to-treat analysis, the decrease in the risk for stroke did not reach nominal significance, he notes, "the study was stopped prematurely for ethical reasons at the advice of an independent data monitoring committee, owing to the significant benefit of active therapy with regard to death from any cause. Although it is unfortunate that the stopping rules for this eventuality were not established a priori, it would have been difficult to continue the study in the presence of a clear effect on death from any cause."

Current practice has been based on incomplete evidence and speculation, Kostis concludes. "The HYVET investigators deserve to be congratulated for persevering and ultimately succeeding in proving the benefit of treating hypertension in the very old."

No J-curve

At the meeting here, the discussant for the HYVET trial was Dr C Venkata S Ram (University of Texas Southwestern Medical Center, Dallas). He noted in particular the finding of a substantial reduction in heart failure and speculated on the economic savings that might result from that effect of treatment.

"What you have shown is that despite very good control of blood pressure, there did not appear to be the so-called phenomenon, the J-curve, in the population you studied, which is very reassuring for aggressive treatment in elderly patients with hypertension," he said.

Important clinical trial data

Asked for comment on the trial results, Dr Philip B Gorelick (Illinois College of Medicine, Chicago, IL), who was not involved in the study, pointed out that whether it is advisable to lower blood pressure and the degree to which BP should be lowered in the very elderly are questions frequently asked by clinicians. "There has been continued concern among practitioners in the field that lowering blood pressure in the very elderly might result in serious adverse outcomes such as death or stroke," Gorelick said.

Although all key outcomes in the HYVET trial did not reach statistical significance, intention-to-treat analysis showed that major end points of interest such as stroke, death from any cause, and heart failure all had relative risk reductions favoring the active-treatment arm, he noted. Furthermore, the treatment was safe.

"HYVET provides important clinical trial data to support the benefit of treating elevated blood pressure for persons in their 80s," Gorelick concluded. He said he is very interested to see the results of the incident dementia study to see how treatment affects the occurrence of cognitive decline or dementia, "in this high-risk population for loss of cognitive vitality."

Dr Robert J Adams (Medical University of South Carolina, Charleston) said the findings from HYVET are "on its face an impressive result of treatment with, for the most part, diuretic and ACE inhibitor, since about 75% of the active-treatment group was on both drugs."

He noted, though, that this was not an American study and that the population of patients was very healthy, with "remarkably" low rates of known cardiovascular disease, diabetes, and heart failure. "The results however, are impressive, and for patients like this, if indeed any of us in the US ever see such healthy older people, the HYVET data support treatment of systolic blood pressure of 160 mm Hg or higher. Although the stroke rates were low, they were more lethal than expected from other studies with younger cohorts," Dr. Adams added. "Overall, the study is of great interest, especially for those with a geriatric practice."

The study was supported by grants from the British Heart Foundation and the Institut de Recherches Internationales Servier. Beckett reports receiving grant support from the Institut de Recherches Internationales Servier.Dr Christopher J Bulpitt ( Imperial College London) reports receiving consulting fees from Imperial College Consulting, a consultancy funded by a grant from the Institut de Recherches Internationales Servier. Disclosures for other coauthors appear in the paper. Kostis reports receiving consulting fees from Pfizer and Sankyo-Forest and grant support from Boehringer-Ingelheim and Pfizer.


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