Support for Combined Administration of Antihypertensive and Lipid-lowering Agents to Reduce Cardiovascular Events - The Emergence of the Multipill

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Citation
US Cardiology, 2006;3(2):1-3

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About 26% of the adult population worldwide has hypertension. In the US adult population, about 30% have hypercholesterolemia and 50-75%, depending on age range, share both. In addition, hypertension and hypercholesterolemia frequently coexist with diabetes, chronic kidney disease, cigarette smoking, obesity and sedentary lifestyle, all of which are potent risk factors for cardiovascular diseases, the most common cause of death in adults in the industrialized world.1 Traditional treatment approaches targeted each modifiable risk factor as an isolated event. At least two observations led to adjustments in this approach. First, the aim of treatment is to reduce cardiovascular events rather than to achieve a level for a particular risk factor. Second, and more importantly, clinical trials such as the Heart Protection Study, the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) and others show that prominent reductions in cardiovascular events, including stroke, occur in patients with moderate to high cardiovascular risk profiles when blood pressure lowering and cholesterol lowering medications are combined, in the absence of a primary indication for both. In these patients, the emerging therapeutic paradigm is to treat the overall level of cardiovascular risk rather than the level of a particular risk factor. The logical extension of this is a single pill aimed at more than one cardiovascular risk.

The first major product to be marketed with this in mind is a combination of amlodipine, a potent antihypertensive, and atorvastatin, a potent cholesterol-lowering agent. At this stage it is not clear if the combined effects are synergistic, but they are at least additive. Additional benefits may arise from reduced cost and improved patient acceptance from simplification.

When Two Is Not Better Than One

From a practical perspective, the biggest problem with the traditional approach was the need for multiple medications, raising spectres of patient compliance and expense.Anything that can truncate costs and improve adherence to daily medications should contribute to the efficacy of the individual medications.

Ideally, all medications that a person needs to take simultaneously would be merged into a single pill. The practical reality of creating such a pill, however, is that you cannot simply 'glueÔÇÖ all the individual agents together; there are technical limitations to overcome. The agents must:

  • be pharmacokinetically compatible;
  • be able to be taken at the same time in the same fasting or non-fasting states;
  • have comparable durations of action and independent metabolic clearances;
  • not interfere with the otherÔÇÖs bioavailability - absorption in the gastrointestinal tract, or hepatic and renal clearance;
  • have acceptable compound pill size; and
  • have comparable shelf-life stability.

 

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References
  1. National Health and Nutrition Examination Survey http://www.cdc.gov/nchs/nhanes.htm
  2. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) , JAMA (2002);288: pp. 2981-2997.
    Crossref | PubMed
  3. Sever PS, Dahlof B, Poulter NR, et al., Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA) , Lancet (2003);361, pp. 1149-1158.
    Crossref | PubMed
  4. Nissen S E,Tuzcu E M, Libby P, et al., Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure.The CAMELOT study: A randomized controlled trial , JAMA (2004);292: pp. 2217-2226.
    Crossref | PubMed