Marlene Busko

December 05, 2014

CHICAGO, IL — Adding the angiotensin-receptor blocker (ARB) olmesartan on top of an ACE inhibitor and/or a beta-blocker did not improve clinical outcomes and in fact worsened renal function in hypertensive patients with stable heart failure, in a large trial conduted in Japan[1].

Dr Yasuhiko Sakata (Tohoku University, Sendai, Japan) presented the findings from this trial, the Supplemental Benefit of an Angiotensin Receptor Blocker in Hypertensive Patients With Stable Heart Failure Using Olmesartan (SUPPORT), at the American Heart Association (AHA) 2014 Scientific Sessions.

SUPPORT also showed that triple combination of olmesartan, an ACE inhibitor, and a beta-blocker was associated with increased adverse cardiac events. "Therefore, we may conclude that [this] triple-combination therapy should be avoided in patients with heart failure," Sakata said.

Finding no overall improvement was "disappointing but not surprising," the assigned discussant, Dr Eric J Velazquez (Duke University, Durham, NC), commented.

SUPPORT was essentially a trial of patients with heart failure with preserved ejection fraction (HFPEF), he said. "Based on guidelines that currently do not recommend any of these medications—ACE inhibitors, beta-blockers, or angiotensin-receptor blockers—in patients who have controlled blood pressure and controlled heart rate, I don't think we're going to have a very large impact on changing those guidelines based on those results," he summarized. The study was, however, a well-conducted multicenter trial, which provides information about the safety of these therapies for a group of patients commonly seen in clinical practice.

Val-HeFT, CHARM-Added, and SUPPORT

"It is still controversial whether the addition of an ARB to an ACE inhibitor and/or beta-blocker is beneficial in heart-failure patients," Sakata said. In Val-HeFT, valsartan decreased the incidence of all-cause death but was harmful when added to an ACE inhibitor and beta-blpcker. However, in CHARM-Added, candesartan decreased the combined end point (cardiovascular death and hospital readmission for CHF) even in the subpopulation that was already receiving an ACE inhibitor and beta-blocker.

Meanwhile, the prevalence of HFPEF is increasing, and "this is a big healthcare problem, because there are no established therapies for HFPEF, Sakata said.

The SUPPORT trial enrolled 1147 hypertensive adult patients with symptomatic heart failure who were being treated with an ACE inhibitor and/or beta-blocker but not an ARB, during 2000–2010.

The patients were randomized to a control group or to receive olmesartan, titrated up to 40 mg/day, and followed for 3 to 6 years.

They had a mean age of 65, and 75% were male. Most were NYHA class 2 (93%) and the rest were NYHA class 3 (7%). Their blood pressure was well controlled; their mean blood pressure was 128/74 mm Hg. A large number were taking an ACE inhibitor (73%) or a beta-blocker (81%).

Olmesartan treatment did not lower the rate of the primary end point of a composite of all-cause death, nonfatal MI, nonfatal stroke, and hospitalization for HF (29.2% vs 33.2%; HR 1.18, 95% 0.96–1.46; p=0.112).

There were no differences in each component of the primary end point or in any secondary end point, except olmesartan worsened renal function in these hypertensive patients with CHF who already had well-controlled hypertension.

In subgroup analysis, adding olmesartan to a beta-blocker alone improved mortality, but adding it to an ACE inhibitor alone did not improve mortality.

Triple therapy was particularly harmful. In the subgroup of patients who were already receiving both an ACE inhibitor and a beta-blocker, adding olmesartan increased the primary end point as well as all-cause death and renal dysfunction.

Sakata acknowledged that patients already had well-controlled blood pressure at study entry and had stable, mildly symptomatic heart failure (median BNP of 80 pg/mL). Relatively few patients had reduced ejection fraction (38% of patients had LVEF <50%).

Nevertheless, SUPPORT provides additional evidence and is consistent with Val-HeFT but not the CHARM-Added trial. This might be explained by differences in severity of heart failure, Sakata suggested. SUPPORT and Val-HeFT included mainly patients with NYHA class 2 HF, whereas CHARM-Added mainly enrolled patients with class 3.

Similar Cohorts in SUPPORT, Other HEFPEF Trials

Velazquez noted that the SUPPORT cohort had "very well-controlled, well-compensated heart failure . . . with very few functional class limitations."

One difference between other trials in HFPEP patients—such as DIG, CHARM, SENIORS, PEP-CHF, and I-Preserve—is that in SUPPORT, only a quarter of the patients were women, whereas 41% to 60% of participants in these other trials were women. Nevertheless, overall, the SUPPORT population compares quite well to HFPEF trials, including TOPCAT, he said.

The main finding was not surprising, because "guidelines don't focus on the need for additional therapy when blood pressure is controlled, and previous trials—particularly PEP-CHF and I-Preserve—have not shown any benefit from the use of ACE inhibitors or ARBs in this population," Velazquez commented.

Importantly, there was a clear signal for worsening renal function with the addition of olmesartan, although the mechanism for this remains to be elucidated.

"There were [also] some additional concerning signals that we can't gloss over—numerically higher cases of new type 2 diabetes, strokes, and sudden cardiac deaths—that suggest that clearly, not only was there no overall benefit, but there may be a signal for harm," he said. The signal from triple therapy, which was well laid out by the investigators, is also concerning.

Sakata and coauthors have reported they have no relevant financial relationships. Velazquez has received research grants from National Heart, Lung, and Blood Institute and Ikaria Pharmaceuticals and acted as a consultant for advisory boards for Novartis.

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