Treating hypertension in the elderly: Expected and unexpected benefits

The results of the Hypertension in the Very Elderly Trial (HYVET) are an emphatic endorsement for treating hypertension in very elderly patients. MedWire reporter Eleanor McDermid discussed the findings with lead investigator Professor Christopher Bulpitt.

Christopher Bulpitt is Emeritus Professor of Geriatric and Cardiovascular Medicine at Imperial College London. He was an investigator on several hypertension trials, including EWPHE and Syst-Eur, before becoming lead investigator of HYVET.

The knowledge gap

Treating hypertension to prevent heart disease and stroke is one of the mainstays of cardiovascular medicine. But before HYVET¹, which began enrolling in 2000, there was one clear gap in the knowledge: How to treat very elderly patients with hypertension.

This knowledge gap was reflected in guidelines. “Most guidelines said that they were waiting for more information, that the situation wasn’t certain,” says Bulpitt.

In fact, the 2004 British Hypertension Society guidelines² explicitly stated that no clear guidance could be given until the results of HYVET were known. The trial is the only randomized antihypertensive trial to have specifically recruited patients aged at least 80 years.

The knowledge gap arose partly because clinical trials tend to initially target patients with the clearest chance of treatment success. But according to Bulpitt: “We should have started with finding what didn’t work.” He believes it would have been more efficient to start by testing the effects of antihypertensive treatment in very elderly patients with relatively moderate blood pressures, and working toward younger patients with more overt hypertension.

“So the trials started in young people and they found benefits,” says Bulpitt. “And then they thought about the elderly, and then people divided into two camps saying, you know, the elderly needed the blood pressure to perfuse their brains.”

He illustrates this by mentioning one general practitioner (GP) who refused to participate in HYVET: “She said it was unethical.”

Her reasoning was that it was dangerous to give antihypertensives to the very elderly because it resulted in excessive postural hypotension and electrolyte disturbance.

“The skill of geriatric medicine used to be said to be knowing which problem to start with.”

Doctors arguing against treating very elderly hypertensive patients were given support by the tendency toward increased mortality among older patients receiving active treatment in hypertension trials.

This was backed up in the HYVET pilot³, where there was “a beautiful balance of every stroke you save, you cause one nonstroke death,” says Bulpitt.

In the second camp were cardiologists and hypertension experts who advocated treating hypertension in the very elderly. But these specialists rarely saw very elderly patients. “The people actually on the frontline, the geriatricians and GPs, weren’t [treating hypertension],” says Bulpitt.

Added to the concerns about a possible negative effect of antihypertensives is the host of other problems related to medicating very elderly patients.

“The skill of geriatric medicine used to be said to be knowing which problem to start with,” says Bulpitt. “They’re just overloaded, you know, they’re taking all these tablets.”

But he adds: “I think the results of HYVET will shift them into perhaps putting hypertension higher up the list.”

Luck of the draw

The results of the HYVET trial contradict previous evidence of increased mortality among very elderly patients given antihypertensives, instead showing a 21% relative reduction in all-cause mortality among those taking active versus placebo treatment.

Bulpitt admits it is difficult to explain this discrepancy, but thinks it could be partly down to the choice of antihypertensive. “High doses of 5 mg of bendrofluazide were commonly used [prior to HYVET], and they will cause electrolyte problems in the elderly,” he explains.

Antihypertensive treatment was also associated with an excess death risk in the HYVET pilot study. But the pilot trial was an open design with a smaller patient population than the main study. It used predominantly lisinopril 2.5 mg and bendrofluazide 2.5 mg.

Bendrofluazide is a diuretic, as is indapamide, the active treatment used in HYVET. But patients in HYVET received an extended-release formulation, so just 1.5 mg per day was as effective as a higher dose of a standard formulation, Bulpitt believes.

Not that this determined the investigators’ choice of drug for HYVET. “The real awful truth is that you use the drug where the pharma industry is willing to provide it, including matching placebos, and all the monitoring and infrastructure that’s absolutely necessary,” says Bulpitt.

The trial was sponsored by Imperial College London, and was partly funded by the British Heart Foundation, a deliberate choice on the part of the HYVET investigators, who wished to remain as independent as possible. But complete funding of a trial on the scale of HYVET is beyond the means of charities and academic bodies.

“So we had to find an industrial partner, and we were very lucky to find Servier, who made [extended-release indapamide], and wanted to test it,” says Bulpitt.

Secondary benefits

Stroke was chosen as the primary endpoint in the trial, rather than all-cause mortality, which was a secondary endpoint, because it has consistently proved to be the clinical endpoint most sensitive to reductions in blood pressure.

As Bulpitt puts it: “The biggest gain for your buck is preventing strokes.”

“At that age, you can’t go on driving a high blood pressure along. Something will happen, either you’ll have a stroke or your heart will fail because it’s a big pressure it’s working under”

Previous trials such as EWPHE⁴ (European Working Party on Hypertension in the Elderly), published in 1985, and Syst-Eur⁵, published in 1997, reported about a 43% reduction in stroke among patients given an antihypertensive versus placebo. The minimum age requirement in these trials was 60 years, so patients were considerably younger than the HYVET participants. The relationship between hypertension and stroke risk becomes weaker as patients grow older, which Bulpitt says is probably because of competing risks. In other words, very elderly patients often die of another cause before they suffer a hypertension-related stroke.

In keeping with this, patients receiving active treatment in HYVET had a smaller, but still significant, 30% reduction in the rate of fatal and nonfatal stroke and a 39% reduction in the rate of death from stroke, relative to patients taking placebo.

But active treatment was also associated with an impressive 64% reduction in the rate of heart failure in the intent-to-treat analysis (which includes patients who dropped out of the trial).

Bulpitt believes that heart failure is fairly inevitable in very elderly hypertensive patients. “At that age, you can’t go on driving a high blood pressure along. Something will happen, either you’ll have a stroke or your heart will fail because it’s a big pressure it’s working under.”

Uncontrolled hypertension is less likely to lead to heart failure in patients in their 60s and 70s, and there have been no trials specifically addressing the issue in octogenarians.

“So even though geriatricians might recognize it – I recognized it – it wasn’t widely known,” says Bulpitt.

Heart failure is a problematic endpoint, being troublesome to define. “We were very particular about that,” says Bulpitt. Patients in HYVET had to have at least two of seven symptoms, and a diagnosis of heart failure was ultimately decided by an independent endpoints committee.

In the per protocol analysis (of patients who completed the trial), active treatment was associated with a 72% reduction in heart failure.

Bulpitt comments: “It just goes to show, you take the pressure off the system and it won’t fail.”

Unanswered questions

Despite the resounding success of HYVET, there are still unanswered questions. This is partly down to increasing lifespan. One reason for the lack of data on antihypertensive treatment in octogenarians prior to HYVET is simply that there were few people of this age around during the time of trials such as EWPHE and Syst-Eur.

“We did have someone of 101 [in EWPHE],” says Bulpitt. “But he didn’t survive the placebo run-in. Things are improving now, so in HYVET we did have someone come in at 105 and actually got randomized.”

But still, the proportion of over-80s in HYVET was small, so the findings relate mainly to octogenarians.

Another issue is target systolic blood pressure. Treatment in HYVET was aimed at achieving a blood pressure of 150/80 mmHg.

“We’re going to do some analyses in the future to say how well people did at different achieved blood pressures,” says Bulpitt. “But maybe we should have gone lower. Maybe we should have said 140 [mmHg].”

Epidemiologic studies indicate that systolic blood pressure of 130 mmHg or lower may be the ideal, he adds.

Reducing blood pressure targets does not exclude patients with isolated systolic hypertension, who comprised about a third of the HYVET cohort, Bulpitt notes. He explains that the effectiveness of antihypertensive treatment is relative to patients’ starting blood pressure. So treating patients with isolated systolic hypertension causes a substantial reduction in systolic pressure but just a small reduction in diastolic pressure.

“It just goes to show, you take the pressure off the system and it won’t fail.”

Hypertension is often defined as a systolic blood pressure of over 140 mmHg, but Bulpitt points out that this is not evidence-based, except in diabetic patients. Indeed, the recent ONTARGET⁶ trial reported that adding an ACE inhibitor to angiotensin receptor blocker therapy further reduced patients’ blood pressure, yet did not enhance cardiovascular benefits. Moreover, patients suffered more side effects if they took both drugs.

Bulpitt says this could show that major blood pressure reduction was not necessary in the ONTARGET cohort, which had an average systolic blood pressure of about 142 mmHg at entry.

“Or you could argue, people need some renin and you can’t knock it all out,” he says. “It just goes to show, there’s still a lot of questions.”

In the meantime, the HYVET findings should prompt an update to the guidelines to include active management of hypertension in very elderly patients.

The HYVET investigators have presented their results to various cardiology, hypertension, and geriatric societies, and the American and European hypertension societies have already indicated that the HYVET results will influence the next guideline updates.

From here, the new advice should hopefully filter down to geriatricians and GPs.