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17th Scientific Meeting of the European Society of Hypertension

Milan, Italy / June 15-19, 2007

As discussed by Dr. Sverre Kjeldsen, Chief Physician, Department of Cardiology, Ullevål University Hospital, Oslo, Norway, the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study randomized 9193 patients 50 to 80 years of age with treated or untreated essential hypertension and ECG evidence of left ventricular hypertrophy (LVH) to losartan (n=4605) or atenolol (n=4588) for at least four years at 945 centres in seven countries in a prospective, double-blind, parallel-group trial. It was designed to determine if selective blockade of angiotensin II would improve ECG-ascertained LVH beyond reducing blood pressure (BP) and reduce cardiovascular (CV) morbidity and mortality to a greater extent than the beta-blocker.

“LIFE is the only large study ever carried out in people with LVH,” Dr. Kjeldsen noted. “They randomly received 50 mg losartan titrated to 100 mg or the same dose of beta-blocker to achieve a BP of 140/90 mmHg or lower. After the second month of double-blind therapy, 12.5 mg hydrochlorothiazide [HCTZ] was added if the BP goal was not reached.” Average baseline BP in both groups was 174/98 mm Hg, which Dr. Kjeldsen said confirms that it does not have to be very high to initiate LVH; it is more a question of long-standing hypertension, he elucidated.

LVH prevalence was similar between the two treatment groups at baseline as measured by elevated Cornell product (65.8% and 65.5% in the losartan and atenolol groups) and Sokolow-Lyon voltages (21% and 21.9%). Using both ECG Cornell products and Sokolow-Lyon voltages as measures of LV mass, Dr. Kjeldsen reported that both decreased significantly (P<0.001) in the two groups after six months of treatment. However, regression of LVH was greater in the angiotensin II blocker treatment group. All patients achieved further regression of LVH over the following 18 months of treatment, with prevalence again lowered to a greater extent among those given losartan (Cornell product -20.5% vs. -12.8%, P<0.001 and Sokolow-Lyon voltage -11.7% vs. -8.5%, P<0.001).

Decreased Cornell product and Sokolow-Lyon voltage were both predictors of reduced risk for CV death, myocardial infarction (MI) and stroke, Dr. Kjeldsen noted. Standard deviation decreases in Cornell product and/or Sokolow-Lyon voltage were associated with a 29.1% lower risk of the composite end point, a 38% lower risk of CV death, an 18.9% lower risk of MI and a 26.8% lower risk of stroke.

A Significant Study

“The LIFE trial emerged as the first large outcome study to achieve a significant difference in designated end points between the two treatment arms,” Dr. Kjeldsen remarked. “The statistical plots diverged early and separated consistently throughout the entire trial. We aimed for a 15% difference between the two arms and finished with 14.6%, clearly a significant accomplishment.”

Although there was a significantly greater benefit regarding stroke among losartan-treated patients compared to the beta-blocker, Dr. Kjeldsen reported that the incidence of MI was not markedly different between the two treatment arms, and difference in outcome did not reach statistical significance.

Regarding stroke, Dr. Kjeldsen indicated that the final outcome in LIFE was driven by a 25% reduction in cerebral stroke, which is beyond what can be achieved with standard beta-blocker/HCTZ treatment. “There should not be any doubt that lowering BP per se protects against stroke,” he stressed. “Losartan reduced the incidence of all strokes, atherothrombotic, embolic and hemorrhagic.” The incidence of fatal stroke was 0.6% with losartan and 2.1% with atenolol (P=0.35). Compared to the atenolol group, losartan-treated patients achieved lower stroke risks in general (40% risk reduction, P=0.02), of fatal stroke (70% risk reduction, P=0.035) and atherothrombotic stroke (45% risk reduction, P=0.022). Among patients who did suffer strokes, those in the AIIA arm had a significantly lower incidence of paresis/paralysis, speech impairment, central cranial nerve dysfunction and memory defects. In hypertensive patients with LVH and atrial fibrillation, losartan significantly reduced stroke incidence by 49%.

Dr. Kjeldsen added that losartan conferred significant clinical benefit on patients with isolated systolic hypertension (ISH), the most common form of hypertension in the elderly. “The drug was more protective against CV mortality and stroke, and decreased all-cause mortality more effectively than atenolol for the same level of BP reduction,” he told delegates. ISH patients achieved an overall 26% reduction in the primary composite end point of CV mortality, stroke and MI when treated with losartan compared to 13% in the overall study population.

Improved BP Control

Dr. Massimo Volpe, Chairman, Cardiology Department, La Sapienza University, Rome, Italy, remarked, “Observational studies reveal that just a difference of 2 mm Hg in some patients can impact on clinical events, and that even within the range of normal BP there is evidence that small improvements can lead to large benefits in risk reduction. Very small differences may be associated with a large difference in outcomes. It is no longer difficult to imagine that a 2 to 3 mm Hg difference can be associated with a large difference in risk for a primary end point.”

He suggested that one reason to expect to see different outcomes from within normal BP range is the duration of most international clinical trials. After five years, differences are rather small but in the long-term Framingham analysis, it became clear that individuals in the high normal BP range were quite different from individuals in the normal range at 12 years of follow-up. Another important lesson from observational studies is that the earlier BP goals are reached, the better the outcome. As Dr. Volpe stated, this implies that hypertension treatment should not be delayed, but started as soon as possible after diagnosis is established.

Pathogenesis

According to Dr. Bryan Williams, Department of Cardiovascular Sciences, University of Leicester UK School of Medicine, an important issue to consider in the treatment of hypertension is its pathogenesis.

“Young people primarily have well-documented vasoconstriction, sympathetic activation, increased peripheral resistance and small-artery remodelling. Older people develop damage to the aorta, stiffening of the aorta, widening pulse pressure, which is a marker of damage, and an increase in systolic pressure which becomes progressively more difficult to treat,” he told delegates.

“In addition, they get small-artery damage to kidneys and declining glomerular filtration rate leading to sodium retention. We should not lose sight of the fact that plasma renin is important early in hypertension, and activation of the renin system has been well documented in many studies in young people with hypertension. Thus we suggest that patients should be treated with drugs that block the renin system as first drug of choice in young people to not only to get better BP control, but also because we believe this would be the most effective strategy to prevent the evolution of damage,” he postulated.

“In older individuals, the evidence supports the fact that initiation of therapy with a calcium channel blocker or a diuretic is likely to produce the most effective BP lowering. But in the elderly, the addition of another drug is usually required to get control. We think that drug should be an angiotensin-inhibiting one.”