In the June 2010 online version of the Lancet Oncology journal, a provocative report of a recently completed meta-analysis suggests that angiotensin receptor blockers might confer a modest but statistically significant increased risk for cancer.

These results were a mixture of both prespecified and non prespecified cancer outcomes in clinical trials where different ARBs were used though telmisartan was the study drug in approximately 86% of patients. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7·2% vs 6·0%, risk ratio RR 1·08, 95% CI 1·01—1·15; p=0·016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1·11 (95% CI 1·04—1·18, p=0·001).

This meta-analysis does suggest a modest but significant link between cancer use and ARBs. However, questions remain. Firstly, is this affect real? Secondly, can we generalize these results to other medications within the ARB class. An important limitation of this study is that much of the data were derived from the occurrence of cancer in patients from the ONTARGET Study in the treatment arm where both ramipril and telmisartan were used; there was no effect seen in the monotherapy arms.*

Many studies have questioned the effectiveness of hydrochlorothiazide (HCTZ) versus chlorthalidone as a diuretic. In fact, most large scale trials that have used HCTZ have been disappointing (e.g. ACCOMPLISH) while those using chlorthalidone have been largely positive (e.g. ALLHAT). While this might seem like an over-simplification, many hypertension experts agree with it.

In the latest twist to this story, Takeda Pharmaceuticals have created a fixed dose combination with it's new ARB azilsartan with chlorthalidone - in stark contrast to all other ARB and ACE inhibitor counterparts. As it it turns out, they may be on to something ( continued ... )

Over the past 2 years, considerable excitement has been building over the results of the ACCOMPLISH study. This trial suggested that the combination of benazapril plus amlodipine is superior to benazapril plus hydrochlorothiazide for the prevention of a composite cardiovacular outcome. While there are methodological concerns regarding this trial that make me question its generlizability, it is thought-provoking to consider that one medication combination is superior to another even if blood-pressure between the 2 groups is negligible.

In the latest issue of Lancet, a follow-up paper suggests that benzapril-amlodipine prevented renal outcomes more-so than in the benazapril-hydrochlorothiazide arm. However, as the excellent accompanying editorial points out, all is not as it appears. (continued...)

By Crystal Phend, Staff Writer, MedPage Today
Published: May 12, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

SAN FRANCISCO, May 12 -- Ambulatory blood pressure monitoring didn't explain the cardiovascular advantage of calcium channel blockade found in the ACCOMPLISH trial, researchers said.

The primary findings of that trial revealed a 20% reduction in cardiovascular mortality and morbidity with the calcium channel blocker amlodipine (Norvasc) versus the diuretic hydrochlorothiazide (Microzide) as the initial antihypertensive in combination with the ACE inhibitor benazepril (Lotensin).

But in a secondary analysis of ACCOMPLISH results, 24-hour blood pressure monitoring revealed no difference in blood pressure control between the regimens, Kenneth Jamerson, M.D., of the University of Michigan in Ann Arbor, and colleagues found.

These results affirm that the calcium channel blocker combination has some "pleiotropic" benefits beyond blood pressure lowering alone, Dr. Jamerson reported at the American Society of Hypertension meeting.
Action Points  

    * Note that guidelines from the National Heart, Lung, and Blood Institute (JNC 7) recommend thiazide-type diuretics as initial therapy for most hypertensive patients, whether alone or in combination with an agent from another class.


    * Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

"It really does matter what agent you use," he said.

After the primary report of the data, concerns had arisen that lower blood pressure in the calcium channel blocker group biased the results, commented co-author George Bakris, M.D., of the University of Chicago, who moderated a press conference at which the findings were presented. (See ACC: Calcium Channel Blocker Beats Diuretic for Initial BP Combo Therapy)

Also, the trial used hydrochlorothiazide rather than the longer-acting diuretic chlorthalidone, which could have meant less blood pressure control over the full 24 hours compared with the other combination regimen.

But the ambulatory blood pressure results lay these questions to rest, Dr. Jamerson said.

"This type of data has the potential to change the paradigm to treat blood pressure from mostly being diuretic-based combination therapy to being amlodipine with benazipril type regimens," he said.

In the analysis of 573 patients in ACCOMPLISH, the in-clinic systolic blood pressure after two years of treatment averaged 0.6 mm Hg lower with amlodipine plus benazipril compared with hydrochlorothiazide plus benazipril (129.7 versus 130.3 mm Hg, P=0.621).

But the 24-hour blood pressure average actually favored the diuretic-ACE combination (122.3 versus 123.9 mm Hg, P=0.128), as did daytime and nighttime averages (P=0.097 and P=0.332).

For diastolic pressure, the diuretic combination also had a small, 0.3-mm Hg advantage over 24 hours (P=0.7).

None of these were significant differences, and both groups attained greater than 80% blood pressure control rates (81.3% with the calcium channel blocker and 84.9% with the diuretic combination, P=0.243).

Dr. Bakris said that a calcium channel blocker may have "pleiotropic" benefits for endothelial function and the atherosclerotic process that may have lowered cardiovascular risk despite similar blood pressure.

However, some at the late-breaking clinical trials session where the research was presented were skeptical.

Marvin Moser, M.D., of Yale University, who moderated the session, cautioned that the conclusions of the trial may have been overstated.

"The weight of data suggests it's the blood pressure level and not the specific drug," he said.

Guidelines from the National Heart, Lung, and Blood Institute (JNC 7) recommend thiazide-type diuretics as initial therapy for most hypertensive patients, whether alone or in combination with an agent from another class.

"Diuretics have held up as well as anything else," Dr. Moser said. "Before we abandon them we need further confirmation."

Another study presented at the same session, on which Dr. Bakris was also a co-author, suggested there was no difference between agents for left ventricular hypertrophy regression. (See ASH: Lower Blood Pressure Trumps Regimen in LV Remodeling)

Dr. Bakris noted that this surrogate endpoint may be important, but doesn't capture broader cardiovascular effects or the more important mortality endpoint.

In the wake of the ONTARGET study, there is a movement away from using ACE and ARBs in combination for hypertension or general vascular protection. However, the combination is still an option for patients with heart failure where the it has been shown to reduce hospitalization. There remains a question whether the combination can reduce the rate of progression in diabetic nephropathy and other kidney diseases. While the ONTARGET study did include a relatetively small number of patients with nephropathy, it was not designed or powered to show a difference in renal outcomes. A new study, the VA-NEPHRON D, is currently underway to examine the effect of lisinopril plus losartan versus lisinopril plus placebo on the progression of chronic kidney disease. A copy of this study design can be found here. This study should shed light on the role of this medication combination in a disease state with a large unmet therapeutic need.

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