The combined use of angiotensin receptor blockers and long-acting calcium channel blockers as an effective approach to hypertension

Hypertension is defined as a systolic blood pressure of >139mmHg or a diastolic blood pressure of >89mm. Once these values increase past 160 and 100 respectively patients are classified as having stage 2 disease. Although there is a growing awareness of cardiovascular risk factors and the need for a healthy lifestyle, people are working longer, exercising less and eating poor diets. This combined with the aging population continues to drive an increasing prevalence of hypertension with the number of patients in the 7 major markets expected to rise from 190 million in 2004 to 206 million in 2012 (for a detailed analysis of the incidence, treatments and markets for antihypertensive therapeutics click here).

Unless there is clinical evidence of target organ damage or clinical cardiovascular disease and/or diabetes, stage 1 hypertension is usually treated by lifestyle modification. High risk stage 1 patients and most stage 2 patients are treated pharmacologically. An estimate based on IMS sales figures indicates that the antihypertensive market was valued at $31 billion in 2003. This market has undergone a period of changes with genericization eroding sales figures for the four major antihypertensive classes - ACE inhibitors, calcium channel blockers, beta blockers and diuretics, although in prescription terms beta blockers and diuretics actually increased. The net growth in the value of the hypertension market over the last five years has been attributable almost entirely to the ongoing rise of the angiotensin II receptor blocker and analysts predict that Diovan (valsartan), the leader of this class, will be leading global antihypertensive by 2007 with estimated sales of $3.3 billion. Generally physicians now appear to prefer angiotensin II receptor blockers over ACE inhibitors due to their superior efficacy and better tolerance. Future developments are expected to focus on the oral renin inhibitors, with Novartis' aliskiren leading the way. It is expected that aliskiren will have its US and EU launch in late 2006 and analysts estimate that sales will exceed $1 billion by 2008 and reach $3.6 billion by 2012.

Despite advances in the treatment of hypertension many physicians remain frustrated by the limited capability of individual antihypertensive agents to lower blood pressure to target levels. It is no longer possible to identify one particular class of drug as the current gold standard, and despite the growth of the angiotensin II receptor blockers and the promise of oral renin inhibitors, there is no superclass medication on the horizon with the ability to treat hypertension effectively using monotherapy. Instead the solution lies with physicians' acceptance of the need to use effective drug combinations earlier in treatment and the use of combination therapy is set to increase significantly over the next 8 years, based on the new guidelines promoting their earlier use and growing acceptance that patients cannot be controlled on monotherapy. The adoption of combination therapies will be accelerated by positive data from clinical trials however few studies have compared the efficacy/tolerabilty of low dose combination therapies with monotherapies; a recent study by Andreadis and colleagues address this shortcoming.

In their Journal of Human Hypertension study, Andreadis et al compare long-acting dihydropyridine calcium channel blockers with angiotensin II receptor blockers in stage 1 and 2 newly diagnosed hypertensives. The efficacy of high-dose monotherapy vs low-dose combinations of the two categories was also compared in subjects with inadequate blood pressure control after conventional low-dose monotherapy. The study was designed to employ ambulatory (24 hour) blood pressure monitoring to avoid experimental artifact that can occur when blood pressure is recorded over shorter periods during physician visits.

The 302 participants were randomized to receive either low-dose long-acting dihydropyridine calcium channel blockers or angiotensin II receptor blockers. If after 6 weeks blood pressure remained uncontrolled (readings had not improved to less than 140/90mmHg) the montherapy dose was doubled OR or a combination of low doses of the initial therapy plus a drug from the other class was introduced. Monotherapy using the initial low dose antihypertensive was only able to control blood pressure in about 50% of patients irrespective of the class of antihypertensive agent employed. Almost 7% of patients treated with low dose calcium channel blockers developed treatment related leg edema and 2% required discontinuation of treatment.

In patients with uncontrolled hypertension, the combination of low-dose calcium channel and angiotensin II receptor blockers produced a significantly greater drop in systolic blood pressure compared to high monotherapeutic doses of either class. Furthermore combination therapy controlled blood pressure in as many as 62% of patients compared to about 40% of patients receiving high monotherapeutic doses of antihypertensive agent. Moreover, treatment modification due to poor tolerance was required more frequently in patients receiving high doses of calcium channel blocker compared to those patients receiving a combination therapy or a high dose of angiotensin II receptor blocker. Treatment modification was required with a similar frequency in the latter two groups.

The present study therefore demonstrates that a combination of low doses of calcium channel and angiotensin II receptor blockers produces improved efficacy as compared to high doses of either class when employed as a monotherapy. A further advantage revealed in this study is that blood pressure variability over a 24 hour period is much less is patients receiving combination therapy compared to those receiving high-dose monotherapy. This study should therefore further convince physicians of the benefits of combination therapies. Consequently the development of single pill therapeutics combining calcium channel and angiotensin II receptor blockers may also represent a useful life-cycle approach for pharmaceutical companies.