Stroke Risk Reduced With Treatment of Prehypertension

Pauline Anderson

December 08, 2011

December 8, 2011 — Patients with prehypertension who take blood pressure–lowering therapy have a highly statistically significant 22% reduced risk for stroke, a new meta-analysis shows.

The reduction in stroke risk observed in the study was "clear-cut," "clinically meaningful," and evident among all classes of antihypertensive drugs studied, said lead author Ilke Sipahi, MD, assistant professor of medicine, Case Western Reserve University, Cleveland, Ohio, and associate director, Heart Failure and Transplantation at University Hospitals Case Medical Center.

"We saw it with [angiotensin converting enzyme (ACE)] inhibitors, we saw it with calcium channel blockers, and we saw it with angiotensive-receptor blockers [ARBs] to a certain extent," Dr. Sipahi told Medscape Medical News. "So this is true finding: the risk is truly reduced."

However, the study results should not change current recommendations regarding blood pressure–lowering therapy, said Dr. Sipahi. "It's not realistic to go ahead and recommend antihypertensive therapy to every single patient with prehypertensive blood pressure levels, but I think our findings have to be discussed extensively within the medical community."

Prehypertension is defined as a blood pressure of 120 to 139 mm Hg systolic and 80 to 89 mm Hg diastolic. Current guidelines recommend lowering blood pressure to 140/90 mm Hg or less.

The study was published online December 8 in Stroke, the Journal of the American Heart Association.

16 Trials in Analysis

The meta-analysis included 16 randomized controlled trials enrolling a total of 70,664 patients. To be considered for the analysis, studies had to have included patients with an average baseline systolic blood pressure of between 120 and 140 mm Hg and a diastolic blood pressure lower than 90 mm Hg. The trials also had to have had at least 1 comparator group treated with placebo, have reported stroke incidence, and used an antihypertensive drug.

Eight of the trials studied ACE inhibitors, 4 studied ARBs, 2 studied calcium channel blockers, 1 had both calcium channel blocker and ACE inhibitor groups, and 1 used an ACE inhibitor and/or calcium channel blocker. Both patients and investigators were blinded to treatment allocation in all but 2 trials (Irbesartan in Heart Failure With Preserved Systolic Function [I-PRESERVE] and Appropriate Blood Pressure Control in Diabetes [ABCD]), which were single-blind.

The analysis found that compared with patients who received the placebo, those taking antihypertensive treatments had a 22% reduction in incident stroke (relative risk, 0.78; 95% confidence interval, 0.71 - 0.86; P < .000001).

To investigate whether a single study was driving the results, the investigators performed a "one-study out" analysis, which confirmed that the risk reduction remained statistically significant when excluding any of the studies.

There was still a statistically significant reduction in stroke risk with antihypertensive therapy when the analysis was extended to patients with even lower baseline blood pressure levels (<130/85 mm Hg).

All Drug Classes

The reduction in stroke risk applied to all classes of antihypertensive therapy. Patients randomly assigned to receive ACE inhibitors or calcium channel blockers had about a 25% decreased stroke risk compared with placebo, whereas those taking an ARB experienced about a 15% reduced risk.

The investigators did not find trials that compared diuretics, alpha blockers, or beta blockers in a prehypertensive population. "So we don't know whether these drugs would have the exact same beneficial effect, in terms of risk reduction effect on stroke, in these patients," said Dr. Sipahi.

The magnitude of risk reduction was not related to average baseline blood pressure levels, baseline stroke risk, history of hypertension, average age, history of diabetes, or statin therapy. There was also no relationship between the magnitude of average blood pressure lowering and the magnitude of risk reduction.

Prehypertension is quite common, occurring in up to 40% of the population, depending on the age, sex, and ethnicity of the population studied. Professional societies do not currently recommend pharmacological treatment for prehypertension because of the lack of prospective, randomized trials examining the effect of antihypertensive therapy to reduce cardiovascular events in this population.

The current analysis concluded that to prevent a single stroke, 169 patients had to be treated with a blood pressure–lowering medication for an average of 4.3 years. This number, said Dr. Sipahi, is "not huge," and is better than the number needed to be treated with a statin to prevent a stroke. It is estimated that 642 patients need to be treated for 5 years with a statin to prevent 1 stroke. "In that regard, antihypertensives are actually more cost-effective compared to statins for stroke in the setting of prehypertension," Dr. Sipahi noted.

If the stroke risk reduction had been closer to 50%, instead of 22%, "then the number needed to treat would be much lower, and we would have a stronger argument for advocating for antihypertensive therapy in all prehypertensive patients to reduce risk of stroke."

As it stands, starting antihypertensive therapy in patients with blood pressures of 120 to 139 mm Hg may be advisable only in relatively high-risk patients with prehypertension, for example, those with a history of smoking, diabetes, or hyperlipidemia, said Dr. Sipahi.

However, for everyone else, such an approach may be "overkill," he said, adding that expanding blood pressure therapy to patients with prehypertension could be tremendously expensive. He also noted that blood pressure drugs can have adverse effects such as hyperkalemia, hypotension, and dizziness, especially in the elderly.

The analysis found no statistically significant decrease in myocardial infarction (MI) with antihypertensive therapy. However, there was a trend toward risk reduction for MI that was mainly driven by ACE inhibitor trials in patients at high risk, such as the Heart Outcomes Prevention Evaluation (HOPE) trial and the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), said Dr. Sipahi.

This, he said, was not surprising. "Stroke is very blood pressure–sensitive, and MI is more sensitive to hypercholesteremia."

Intense Relationship

Asked to comment, Richard Atkinson, MD, director of neuroscience education, Sutter Medical Center, Sacramento, California, said the study continues to show the intense relationship between blood pressure and stroke and is a reminder that even people with relatively low blood pressures should take steps to improve their stroke risk.

"The message is not that people like me with a blood pressure of 125 should be taking medicine, it's a lifestyle reminder that even though we're comfortably in the nonmedicine range, we can all improve by exercise, weight loss, watching our alcohol intake, and watching our salt intake."

Although he said the analysis "adds support to the idea that prehypertension is real," Dr. Atkinson said he does not think it changes current suggestions in terms of introducing blood pressure–lowering therapy.

He emphasized that the analysis pertains to primary prevention, not secondary prevention. "We're still doing studies to determine how safe it is to lower blood pressure after you've had a stroke."

The study received no outside funding. Dr. Sipahi received an honorarium from Ranbaxy. The other authors have disclosed no relevant financial relationships.

Stroke. Published online December 8, 2011.


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