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.

21st Scientific Meeting of the International Society of Hypertension

Fukuoka, Japan / October 15-19, 2006

According to a recent article by Wong et al. (Am J Cardiol 2006;98(2):204-8), the overall prevalence of hypertension in a representative US cohort of over 2800 participants was 30%, while the overall prevalence of hypercholesterolemia was 47%. The combined prevalence was identified in 18% of the same cohort, both risk factors being slightly more likely to occur in women than in men.

In this survey, 29% overall were receiving treatment for hypertension and hypercholesterolemia, but only 9% of patients had both conditions well controlled. As the authors concluded, treatment and control of combined hypertension and hypercholesterolemia is suboptimal in the US. Given that hypertension control rates are actually better in the US than in Canada, it is imperative to increase every effort to offer proper treatment to patients with both condition.

From Treating Individual Risk Factors to Treating Global Risk

Gaining interest is the concept of combination therapy in one tablet for the overall management of cardiovascular disease (CVD) risk. One such strategy is the combination of a calcium channel blocker (CCB) for hypertension control and a statin to reduce hypercholesterolemia.

“The name of the game isn’t treatment of hypertension or treatment of hypercholesterolemia as much as reducing CVD risk,” essentially a “global atherosclerotic risk,” explained Dr. Ross Feldman, Cell Biology Research Group, Robarts Research Institute, and Professor of Physiology and Pharmacology, University of Western Ontario, London. With two medications in a single pill targeting two key atherosclerotic risk factors, the new single-tablet combination can be thought of as “an atherosclerotic risk-lowering drug,” noted Dr. Feldman, to help physicians “make the conceptual leap from treating individual risk factors to treating global risk.”

This “conceptual leap” was recently tested in GEMINI-AALA, a 14-week study in which a single-tablet amlodipine/atorvastatin combination was evaluated in a 1649-member cohort of patients from a variety of ethnic backgrounds, including Asia-Pacific, the Middle East, Africa and Central/South America. Eight dosage strengths of the single-tablet formulation were titrated up to reduce BP and LDL-C to target levels; the average dose was 6.1 mg of the CCB and 17.1 mg of the statin.

Patients were stratified into cohorts based on their ascending Framingham risk score for coronary artery disease (CAD). All patients had hypertension and dyslipidemia at baseline. Group 1 had no additional CV risk factors, Group 2 had one or more additional CV risk factors (excluding CAD and diabetes), and Group 3 had either CAD, diabetes or their risk equivalent. BP and LDL-C goals for the three cohorts were <140/90 mm Hg and <4.1 mmol/L, <140/90 mm Hg and £3.4 mmol/L, and <130/80 mm Hg and £2.6 mmol/L.

The primary end point was the percentage of patients who achieved BP goals as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure and LDL-C goals as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines.

At study end, 55.2% of patients across all three treatment groups had achieved both BP and LDL-C goals. In the lowest risk group, 81.3% achieved both goals.

In Group 3, the most difficult to treat, highest-risk patients assigned more aggressive treatment goals (i.e. <130/80 mm Hg and £2.6 mmol/L), combination therapy permitted 40.3% to reach their targets at week 14. In the three groups combined, 61.3% achieved BP goals and 87.1% achieved LDL-C goals.

Figure 1. Absolute change in BP and LDL-C over the study period

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Both BP and LDL-C goal attainment was similiar for Asians and non-Asians. The single-tablet combination was also safe and well tolerated, with only 3.6% of the cohort discontinuing treatment due to an adverse event, the most common being peripheral edema (10%).

Based on reductions in both BP and LDL-C achieved in this 14-week study, investigators calculated that the cohort’s 10-year Framingham risk of having a CVD event could be reduced by 54%.

CASE-J Results

Another study presented here confirmed the overall efficacy and safety of amlodipine in a high-risk Asian population. CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan) was designed to compare the ability of the CCB and the angiotensin II receptor blocker (ARB) candesartan to reduce the incidence of CV morbidity and mortality in a Japanese cohort of 4700 high-risk hypertensive patients. Patients were titrated up to amlodipine 5 mg/day or candesartan 8 mg/day, and both arms could receive additional antihypertensive agents to reach target BP goals. The primary end point was a composite of CV morbidity and mortality including sudden death, CV events, cardiac events, renal events and vascular events.

At a mean follow-up of 3.2 years, mean BP reduction from baseline of approximately 162/92 to 133/76 mm Hg for both treatment arms was observed and BP control was virtually identical throughout the study. Nor was there any statistically significant difference in the primary composite end point or in any of the individual components of the composite end point between the two arms.

However, there were differences in time-specific CV events between the two compounds. Fewer events between six and 18 months occurred in the CCB arm and after 18 months, there were fewer events in the ARB arm, although differences were not significant. The incidence of new-onset diabetes was also lower in the candesartan arm, an effect seen with other ARBs and ACE inhibitors.

Interestingly, the time-specific findings in CASE-J mirror those from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study where amlodipine was associated with fewer strokes, myocardial infarctions and deaths within the first few months of the study. By the end of VALUE, there was no difference in the primary composite cardiac end point nor all-cause death.

Dr. Feldman characterized CASE-J as “a smaller Asian version of VALUE.” Although the ARBs and their dosing regimens were different in the two studies, patients had similar overall risk. BP control was better matched in CASE-J than VALUE, where the CCB was associated with greater early reductions in BP, which remained lower by 1 to 2 mm Hg throughout the trial. “CASE-J involved a much smaller patient population but that notwithstanding, results were a confirmation of the VALUE findings; namely, with comparable BP-lowering, you get comparable or at least presumably comparable reductions in CV risk,” Dr. Feldman stated.

Summary

Findings from the GEMINI-AALA study suggested that the single-tablet amlodipine/atorvastatin combination may help bring more patients to goal compared to co-administration of the parent compounds. If further studies support this, targeting two key CVD risk factors in a single combination tablet has clear potential to improve global CVD risk management and reduce long-term CVD risk in hypertensive patients with other risk factors.