Is It Time To ACCELERATE Or Slow Down?

Written By

William D. Linn, Pharm.D.

Reviewed By

Christine Choy, Pharm.D., BCPS
Maria Pruchnicki, Pharm.D., BCPS


Brown MJ, McInnes GT, Papst CC, et al. Aliskirin and the calcium channel blocker amlodipine combination as an initial strategy for hypertension control (ACCELERATE): a randomized, parallel-group trial. Lancet published online January 13, 2011.

One in 3 adults in the United States have high blood pressure (HBP).1 That’s more than 74 million people!  From 1996 to 2006 the death rate due to HBP increased 19.5%. In those with hypertension, blood pressure (BP) control is poor.  In men, less than 40% are achieving their blood pressure goal.  In women, the percentage who are control is even worse.  In women age 60-79 years old only 28% are at their target BP and in women over 80 years old only 23% are at goal.2 Achieving a target BP is obviously a problem and many guidelines recommend initial combination therapy if the patient needs ≥ 20 mmHg reduction in their systolic blood pressure (SBP). But which combination should be used? The landmark trial, ACCOMPLISH, provided important data indicating that achieving a target BP with combination therapy was not enough.3 Major adverse cardiovascular events (MACE) were lower with the angiotensin converting-enzyme inhibitor (ACEI) + amlodipine regimen versus a traditional diuretic-based regimen despite virtually identical (<1 mmHg SBP difference) blood pressure control.  Leaving us to wonder ‑  is blood pressure reduction a valid surrogate outcome to predict MACE? Perhaps it is not whether you reach your target BP but rather how!

Initial combination therapy of hypertension may provide clinical benefits by quickly achieving BP targets. Early differences in BP control may lead to long-term response rates. Brown and colleagues recently published the results of the Aliskirin and the Calcium Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension (ACCELERATE) trial.4 The authors performed a double-blind, randomized, parallel-group, superiority trial in 146 sites in ten countries (Canada, Costa Rica, France, Germany, Greece, Guatemala, South Africa, Switzerland, the UK and Venezuela). Men and women aged 18 years and older with seated SBP between 150 and 180 mm Hg and diastolic blood pressure (DBP) < 110 were eligible. Subjects entered into a 2 to 4 week placebo run-in phase during which existing antihypertensive medications were stopped. The study consisted of three sequential phases of double-blinded active treatment. In phase 1 (weeks 0 to 16), half of the patients started monotherapy with either aliskirin (150 mg) or amlodipine (5 mg) and the other half started a combination regimen of aliskirin (150 mg) plus amlodipine (5 mg). At 8 weeks the doses of each were doubled. In phase 2 (weeks 16 to 24), all patients received the same combination of aliskirin (300 mg) + amlodipine (10 mg). During the final phase (weeks 24 to 32), patients received the addition of hydrochlorothiazide (HCTZ 12.5 mg) or placebo depending on their BP (SBP > 140 mm Hg or DBP > 90 mm Hg). There were two sequential primary endpoints; the first, a mean reduction from baseline of SBP over weeks 8, 16, and 24, testing for superiority between the initial combination regimen versus each of the monotherapies. The second hypothesis ‑ tested if the first hypothesis was positive ‑ was SBP reduction at week 24 greater in patients initially treated with combination therapy?

Twelve hundred fifty four patients were randomized: 318 to aliskirin, 316 to amlodipine, and 620 to combination therapy. The average age of the cohorts was 58 years, approximately half were women, and most were white (77 to 79%). Five hundred patients had newly diagnosed HBP.  The baseline SBP in all groups was ~ 161 mm Hg and was not statistically different. The mean adjusted reduction in SBP from baseline compared to weeks 8 to 24 was 25.3 mm Hg in the combination group and 18.9 mm Hg in the monotherapy groups (p<0.0001). At week 24 when all patients were on a combination of aliskirin 300 mg daily plus amlodipine 10 mg daily, the cohort initially assigned to combination therapy had a SBP 1.4 mm Hg lower than the cohorts initially treated with monotherapy (p=0.059). Patient withdrawals due to adverse events occurred in 14% of the initial aliskirin plus amlodipine group, 14% of the aliskirin monotherapy group, and 18% of the amlodipine monotherapy group. The authors concluded that initial combination therapy using aliskirin plus amlodipine could be recommended in patients whose baseline SBP was > 150 mm Hg.

So what does this all mean and how should it impact our practices? We now know that BP reduction per se is not a perfect surrogate outcome for MACE.  Even some of our “gold standard” drugs such as beta-blockers and hydrochlorothiazide are no longer recommended as first-line therapies.5,6  It seems reasonable to recommend initial combination therapy when the patient’s baseline SBP is ≥ 20 mmHg above goal.  Indeed, there are data to support the contention that achieving BP control in the first three months after starting therapy is beneficial in decreasing cardiovascular events and all-cause mortality when compared to delayed control.7  But there is no outcomes data to support the initial use of aliskirin in any patient population.  What do you think?  Is it time to ACCELERATE or slow down?  I think we need to reassess what we really know about treating high blood pressure!



Thanks to Bill for the very informative review. I would suggest that this is one time when we should NOT ACCELERATE; but rather back up and be happy with our ACCOMPLISHments until someone proves that something else is better. &nbsp;We were a site in the ACCOMPLISH trial - a triel that I believe achieved a higher level of BP control than any study has before (I believe that we had all of the patients in our site at goal BP)....yet the ACE + CCB combo group had a significantly lower major CV event rate than did the ACE + thiazide combo group with identical BP control (as Bill pointed out). The results of that trial are why I chose benazapril + amolodipine for a family member who recently developed persistent hypertension. So why don't we hear more about ACCOMPLISH? Because Novartis lost its intellectual property protection earlier than anticipated so that they had no incentive to promote the AHA/ACC/ACCP meeting symposia on this study. Something is wrong with our system when such impressive results come out of a huge, well-designed, and well-executed study.....but then the results go relatively unheralded. Now....except for the fact that Novartis chose HCTZ rather than Chlorthalidone (Bob Talbert and I were unable to change that choice)....let's hear the opposing views. WHY shouldn't benazepril + amlodopine be the first choice for most of our HTN patients?

I agree with the comments, but I caution against using benazepril + amlodipine as starting HTN therapy when there are older, cheaper, and proven medications on the shelf. Now, this study may prove to be right along if it is included in the next lets say JNC-8? guidelines.