Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

First International Conference on Hypertension, Lipids, Diabetes and Stroke Prevention

Paris, France / March 30-April 1, 2006

“There is a very strong linear relationship between systolic blood pressure [SBP] and the incidence of stroke and it starts already at a SBP of 115 mm Hg,” Dr. Jan Staessen, University of Leuven, Belgium, told delegates here at the First International Conference on Hypertension, Lipids, Diabetes and Stroke Prevention. Experts agreed that reducing SBP to optimal levels is critical for stroke prevention. According to investigators, there is ample evidence indicating that even modest reductions in BP significantly reduce the incidence of stroke.

In the primary prevention setting, randomized clinical trials have consistently shown that active treatment reduces stroke risk by 30% to 40%, even when the difference in BP between active treatment and placebo was only about 10 mm Hg, “and we can do much better today with new drugs than just a 10-mm Hg reduction, so this 30% reduction in stroke could be very much greater,” Dr. Staessen suggested. (Indeed, it was later suggested that a 20-mm Hg reduction in BP would lower stroke risk by about 50% and that this pertains to all individuals, not just to hypertensive patients.) Furthermore, in high-risk patients, even as small a reduction in BP as 3 mm Hg can reduce fatal and non-fatal stroke by about 25% to 30%, while among patients who have already had a cerebrovascular event, antihypertensive treatment reduces stroke occurrence by approximately 40%.

Ideally, treatment should be initiated immediately or as soon as possible following the diagnosis of hypertension, “because if we delay treatment, then a lot more stroke will occur that should not have occurred and we should try to treat to target,” Dr. Staessen warned. He added that going from an optimal BP to a high normal BP “carries exactly the same risk as going from optimal BP to hypertension, so this means we should keep our patients in the optimal range, which is 120 mm Hg.”

Exploring the Evidence

Whether or not one pharmacologic antihypertensive class provides greater protection against stroke than another was discussed by Dr. Xavier Girerd, Division of Internal Medicine, Broussais Hospital, Paris, France.

The literature suggests that the thiazide diuretics do confer particular protection against stroke, at least compared with ACE inhibitors and beta blockers. According to researchers, beta blockers do not appear to provide as great a protective effect against stroke as other classes, nor do the ACE inhibitors. Speakers differed on whether calcium channel blockers (CCBs) decreased stroke risk more effectively than other classes but if this is the case, the additional small benefit provided by a CCB may be explained by its ability to reduce BP to a greater extent than at least ACE inhibitors.

Probably the strongest evidence supporting an additional protective benefit for primary stroke prevention beyond BP control has emerged from the LIFE (Losartan Intervention for End Point Reduction) trial. LIFE findings indicated that the angiotensin receptor blocker (ARB) losartan reduced the risk of stroke by 25% compared with the beta blocker atenolol for identical reductions in BP. As pointed out by Dr. Faiez Zannad, Université Henri-Poincaré, Nancy, France, losartan not only reduced the incidence of stroke in LIFE by 25% compared with atenolol, but there was also a 13% greater reduction in cardiovascular (CV) death, stroke and myocardial infarction in the losartan arm, “so a very impressive reduction in events,” he observed.

Furthermore, the ARB reduced the incidence of new-onset atrial fibrillation by 33% (relative risk 0.67) compared with the beta blocker and there was a delay of slightly more than one year in the occurrence of new atrial fibrillation in the ARB cohort. This result may be attributed to the ARB’s effect on the size of the atria, where over the course of the study, “there was a very important remodelling in the atria and regression was much more pronounced in the losartan group than in the atenolol group,” Dr. Zannad reported.

Regression in left ventricular hypertrophy—an inclusion criteria in LIFE—was also significantly more profound in the losartan arm compared with the atenolol arm. Based on the Echo-Substudy in LIFE—the largest hypertensive echocardiographic study ever carried out in any hypertension trial—investigators showed that for every reduction of 25 g/m2 in left ventricular mass (LVM), there was a 20% reduction in the composite end point, a 34% reduction in CV mortality and a 22% reduction in stroke. Throughout the trial, larger changes in grams of LVM were consistently documented in the losartan arm compared with atenolol arm, again for similar reductions in BP.

The ARB also had a more profound effect on intima-media thickness regression than did atenolol, “so there is a consistently superior effect of angiotensin II receptor blockade—in this case, losartan—compared with atenolol when it comes to remodelling, whether it is in the atria or in the vasculature,” Dr. Zannad stated.

Commentary

Asked to comment further on the protective benefit of the ARB on stroke, Dr. Björn Dahlöf, Director, Clinical Trials Unit, Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden, principal investigator of LIFE, said in an interview that “the stroke story is an added benefit to its many other properties.”

“There are many reasons to prescribe an ARB,” he indicated. Tolerability is of course paramount, he said, and losartan demonstrated “excellent tolerability” in LIFE. Again referring to LIFE, “if you take all of the surrogate end points—the effect of losartan on atrial fibrillation, its effect on intima-media thickness, its effect on LVH and its effect on diabetes [over a 20% reduction in new-onset diabetes compared with atenolol]—outcomes were always better with the ARB than with the beta blocker, so in my mind, you can make a very strong case for losartan, and not just for stroke,” Dr. Dahlöf said.

He also noted that it is his philosophy that physicians should find the best available treatment for each patient and cost considerations should be secondary. Canadian experts would appear to agree, as the ARBs as a class are indicated as first-line therapy for the treatment of hypertension, according to new Canadian guidelines, and are not restricted to patients who cannot tolerate an ACE inhibitor.

“We do not have another confirmative study other than LIFE, and there probably will not be as LIFE was such a strong study and we do not want to put patients to the same test again,” Dr. Dahlöf said. “But by inference, it has been my experience [as an investigator] that ACE inhibitors are less protective against stroke than the ARBs for the same BP control. So everything supports the finding that the stroke effect in LIFE is real.”