How low can you go with blood pressure?

A US study has done little to resolve the question of whether to aggressively treat HT in low risk patients

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A new US study has done little to resolve the question of whether to aggressively treat hypertension in lower-risk individuals

How aggressively to treat hypertension in adults without pre-existing heart disease has been the million-dollar question in the field for at least the past decade.

Back in 2007, a US National Heart, Lung, and Blood Institute expert panel said the question of whether a lower systolic target of 120 mmHg would reduce cardiovascular events more than treating to standard targets was the most important untested hypothesis in the area of hypertension.

While antihypertensive therapy has been clearly shown to reduce the risk of cardiovascular disease among people with pre-existing heart disease, renal disease, diabetes or a systolic blood pressure of over 160 mmHg, the value of treating a level of between 120 mmHg and 160 mmHg is less clear.

The answers to these questions have been a long time coming, and the past six months has seen the publication of several long-awaited trials designed to answer them, including the SPRINT and HOPE-3 studies.

The SPRINT trial, published in the NEJM in November last year, found that lower was better when it comes to treating adults with a high risk of cardiovascular disease.

It found that among adults over 50 years with hypertension (but not diabetes), lowering systolic blood pressure to a target of 120 mmHg, as compared to the standard goal of 140 mmHg, resulted in significantly lower rates of fatal and non-fatal cardiovascular events and death from any cause.

As to the second question – whether to treat those with blood pressure less than 160 mmHg at intermediate risk – this was at the heart of HOPE-3 trial, also published in NEJM last month.

Researchers split 12,700 people with intermediate risk but no diagnosed cardiovascular disease into two groups, with one group receiving antihypertensives for five and a half years and the other receiving placebo.

“Intermediate risk” was defined as having a 1% chance of experiencing a major cardiovascular event in one year, and included smokers, people with a low HDL, a family history of heart disease, and mild renal dysfunction.

Extending across 228 centres in 21 countries, the HOPE-3 participants were over 55 years of age and had an average blood pressure at trial entry of 138/82 mmHg.

The results of the double-blind, randomised trial were clear-cut; overall there were no significant differences in the rate of major cardiovascular events, namely heart attacks, strokes and death, between the two groups.

When broken down by initial blood pressure, those over 140 mmHg benefited from treatment but those below did not – and treatment was harmful for some.

The regimen – 16 mg per day of candesartan and 12.5 mg per day of hydrochlorothiazide – was effective in lowering blood pressure, reducing it by 6/3 mmHg over 5.6 years on average.

However, active treatment was also associated with a slightly higher risk of symptomatic hypotension, dizziness and lightheadedness.

So how to interpret HOPE-3 after SPRINT? At first glance, it might seem the findings of the two trials are contradictory.

But according to the principal investigator of HOPE-3, it is important to recognise the trials set out to answer different questions in different populations.

“SPRINT targeted a high-risk population, we targeted intermediate risk,” the author said.

“In SPRINT, most patients were already receiving antihypertensive therapy, while patients in HOPE-3 were not receiving treatment prior to the trial. SPRINT and ACCORD suggest that high-risk patients can derive modest additional benefit from more-aggressive treatment as opposed to less-aggressive treatment.”

According to Sydney cardiologist, Professor Andrew Sindone, the HOPE-3 trial used an inappropriate drug given the outcomes it was looking at. Recent meta-analyses have shown the drugs used in the study were not as effective as angiotensin-converting-enzyme inhibitors.

“Angiotensin receptor blockers [such as candesartan] don’t improve survival,” he said. Neither did hydrochlorothiazide diuretics.

As well, Professor Sindone said patients in the study were too low risk for the average six-point reduction in systolic blood pressure to show any effect on clinical outcomes. Moreover, 23% of participants were not on the drugs by the end of the trial, which further handicapped the study.

Epidemiologist, Professor Jenny Doust from Bond University agreed, saying the study subjects would be considered low-risk by local standards. The study participants had a 5% risk over five years (1% each year). In Australia, generally only patients with a higher risk would be treated.

The HOPE-3 trial massively lowered the threshold for treatment compared with Australia’s National Vascular Disease Prevention Guidelines, she said.

This meant HOPE-3 struggled to show the positive effects of lowering blood pressure, as there were few cardiovascular events and deaths in both the placebo and the treatment group.

The SPRINT trial had the same sort of problems, she said, despite studying higher-risk individuals. Out of every 1000
patients treated, only six deaths were prevented, but there were 18 cases of renal failure or acute kidney injury and six cases of syncope.

“So you’ve got quite severe adverse events,” she said. “So even though the overall primary outcome is statistically significant, again you’ve got to weigh it up.”

SPRINT and HOPE-3 both set targets for blood-pressure reduction, but this in itself creates difficulties, according to Professor Doust.

Blood pressure is an intrinsically “noisy” measurement, and meeting the target often requires adding in a second blood-pressure agent, which increases the risk of side effects, adverse events and reduces adherence to medication.

Moreover, hitting targets may not pay off in the long run as the clinical benefits of intensifying treatment are likely to be small.

Professor Sindone said an advantage of the SPRINT study was that it mirrored real-life treatment. While HOPE-3 researchers gave the same dose to each patient for five and a half years, SPRINT changed the dose depending on the patient’s response.

“[SPRINT] actually got the doctors to check the blood pressure and to titrate the medications to get the target,” he said.

Instead of having patients take the maximum dose of two blood pressure-lowering medications, as in HOPE-3, SPRINT allowed doctors to titrate the dosage of medications and stop them if severe side effects developed and remain in the trial.

“I read [the HOPE-3] study and tossed it in my intellectual bin,” said Dr Sindone. “In terms of treating people of intermediate risk being a waste of time – this study doesn’t help us.”

Professor Sindone has received honoraria, speaker fees, consultancy fees, is a member of advisory boards or has appeared on expert panels for: Abbott, Aspen, Astra Zeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol Myer Squibb, CSL, Jansen Cilag, Menarini, Merck Sharp and Dohm, Novartis, Pfizer, Sanofi Aventis, Servier, Vifor.

Professor Jenny Doust is funded by a NHMRC program grant.