SYST-EUR 2: Benefits of lowering systolic blood pressure are maintained long-term

September 04, 2003

Vienna, Austria - The benefits of the SYST-EUR trial, which showed that treatment of systolic hypertension reduced the rate of stroke by 39% in the elderly, have been maintained in a four-year follow-up to the study, known as SYST-EUR 2, presented at the European Society of Cardiology Congress 2003.

SYST-EUR was a randomized, double-blind trial comparing antihypertensive treatment with placebo in elderly patients with isolated systolic hypertension. Treatment was begun with the calcium channel blocker (CCB) nitrendipine; add-on therapy with enalapril and/or hydrochlorothiazide was then allowed. The trial was stopped in 1997 because treatment was shown to significantly prevent stroke, the primary end point. Results were subsequently published in the Lancet and later updated in Hypertension.

Follow-up continued after study halted

After the halt of study, the SYST-EUR investigators continued to follow these patients, still comparing those who were on active treatment from the start of the trial with those who began treatment only after it was stopped (active-active patients vs placebo-active patients). Dr Robert H Fagard (Catholic University of Leuven, Belgium) told delegates that the aim was to evaluate the long-term outcome of the SYST-EUR patients and the safety of chronic treatment with a dihydropyridine calcium channel blocker. The report extends follow-up from two years in the double-blind trial for a further four years, to give a total of six years of follow-up. In all, 4695 patients participated in the original two-year study; 3517 went on to the extended phase, with nonsupervised, open-label follow-up of the remaining patients.

At follow-up, the relative risk of the primary end pointstrokewas still 28% lower in the patients who had been on active therapy throughout the six years of the trial, compared with the original placebo group (p=0.01). In addition, cardiovascular events were also significantly lower in those who remained on active therapy for the entire six years.

All cardiovascular events in SYST-EUR 2*

Study phase

Placebo-active patients**

Active-active patients**

Difference (% relative risk reduction)

p

Double-blind (2 years)

34.7 25 28 0.002

Extended follow-up

23 22.8 -1 0.96

Total

28.5 24.3 -15 0.03

*Includes sudden death, nonfatal and fatal stroke, myocardial infarction and heart failure
**Event rates per 1000 patient years

"The early benefit observed in the double-blind phase of the study was maintained through extended follow-up," Fagard said. "Once all patients received active study medication, rates became similar in subjects initially randomized to placebo or active treatment, but this trial design inevitably led to some dilution of the original effect of medication on stroke and cardiovascular events," he commented to heartwire .

 
The early benefit observed in the double-blind phase of the study was maintained through extended follow-up.
 

In addition, no increase in adverse events that have been associated with CCB—ssuch as cancer, gastrointestinal problems, hemorrhage, MI, and dementia—was seen, he noted.

Study "unique" but there is a failure to translate the data to the real world

Discussing the results, Dr Frank Ruschitzka (University Hospital, Zurich, Switzerland), said SYST-EUR 2 was "unique among large studies in showing organization of extended follow-up and confirms the benefit of lowering systolic blood pressure in the elderly."

"The results also help to put to an end the long-lasting safety debate about long-acting calcium channel blockers," he noted.

"It is clear that systolic blood pressure has a linear relation with cardiovascular events," he continued, adding, "this is already textbook medicinewe know we must treat 26 patients to prevent one cardiovascular event and 48 patients to prevent one stroke." However, "we fail to translate this data into the real world," he lamented. "We have to increase efforts to get this message acrossthat is why long-term follow-up of studies such as this are so helpful."

 
We fail to translate this data into the real world. . . . We have to increase efforts to get this message acrossthat is why long-term follow-up of studies such as this are so helpful.
 

He noted some limitations of SYST-EUR 2, such as the fact that there was no control group for the extension phase of the study and the fact that the two groups were not identical at the start of follow-up. "I would also like to see follow-up of some of the subgroups in this study," he said, noting that one interesting group would be those with low diastolic blood pressure (<70 mm Hg). "Are these patients higher risk?" he wondered. Nevertheless, these results reinforce the message that "it is safe to treat octogenarians and the very old," he said.

He concluded that debate about which antihypertensive drug to start therapy with was "academic, because these patients need two or three medications anyway." All the antihypertensive drugs "have their place."

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