Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

55th Annual Scientific Sessions of the American College of Cardiology

Atlanta, Georgia / March 11-14, 2006

The benefit of blocking the renin-angiotensin system (RAS) to prevent cardiovascular (CV) events was first confirmed more than 10 years ago with a series of studies conducted with ACE inhibitors. These trials demonstrated protection against events in patients with ventricular damage associated with myocardial infarction or heart failure. Subsequent studies with angiotensin-II receptor blockers (ARBs), which block angiotensin at its receptor and are better tolerated, showed similar degrees of protection on the same hard end points. Initially, there was substantial doubt that these agents would provide additive benefit when used together because they both block the effects of upregulated RAS. However, several studies have now confirmed added protection. On the basis of new analyses requested by the U.S. Food and Drug Administration (FDA) for data from one of these trials, the labelling of the study agent has been changed to reflect independent and additive benefits from an ARB and an ACE inhibitor.

As explained by Dr. Marc A. Pfeffer, Brigham and Women’s Hospital, and Professor of Medicine, Harvard Medical School, Boston, Massachusetts, “The trial already suggested additive benefit, but the FDA wanted us to look deeper to rule out other possible explanations for the results. When we looked deeper, we obtained even more compelling evidence of an additive effect. What we found was that the addition of an ARB will improve outcome in patients with heart failure even when they are on what can be reasonably considered to be a maximum dose of an ACE inhibitor.”

CHARM-Added, the Source

The new analyses were conducted with data generated from the CHARM-Added study in the CHARM (Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity) trials programme. CHARM-Added consisted of 2,548 patients with a left ventricular ejection fraction (LVEF) £40% and New York Heart Association (NYHA) class II to IV heart failure who were already receiving an ACE inhibitor. Patients were randomized to placebo or to the ARB candesartan at 4 to 8 mg and titrated up to 32 mg (or the maximum tolerated dose). The groups were then compared for the primary end point of CV death or hospitalization for worsening heart failure. The addition of the ARB in a patient population already on an ACE inhibitor produced a 15% (P=0.011) reduction in CV events compared to ACE inhibitor monotherapy.

Although the risk reduction in CHARM-Added was less than that achieved with the ARB in CHARM-Alternative, another of the trials in the CHARM programme, patients in CHARM-Alternative were not taking an ACE inhibitor. While CHARM-Alternative associated the ARB with a 23% reduction (P=0.0004) in the primary end point of CV death or heart failure progression relative to placebo, the 15% reduction in CHARM-Added was achieved on top of the ACE inhibitor, a result demonstrating an additive effect.

Determining Benefits

As Dr. Pfeffer explained to delegates, “What the FDA wanted to know was whether patients were actually receiving the optimal dose of ACE inhibitor. One of the questions they asked us to address was whether the same effects might have been achieved by simply increasing the ACE inhibitor dose rather than adding candesartan.” Essentially, the regulatory authorities were asking the CHARM investigators, which included Dr. Pfeffer, to verify that the added benefit of the ARB could truly be attributed to an effect that was not achievable on ACE inhibitor monotherapy.

Pre-specified data collection in CHARM-Added for the type of ACE inhibitor and dose taken at baseline and during follow-up permitted the investigators to address this issue. Noting that CHARM-Added investigators had been supplied with a list of ACE inhibitors and the target maximum doses, Dr. Pfeffer indicated that the data verified that these goals were largely achieved. In particular, average ACE inhibitor doses reached those levels proven effective in key studies that established their benefit in heart failure, such as SOLVD (Studies of Left Ventricular Dysfunction) and CONSENSUS (Cooperative New Scandinavian Enalapril Survival Study).

However, at the request of the FDA, the probing of the data went even further to confirm that ARBs were contributing a unique benefit. In another analysis, the data were stratified by several different criteria to tease out differences in benefit from the ARB at different starting or maintenance doses of ACE inhibitors. For example, one of the most potentially revealing analyses was the effort to determine whether there was diminishing benefit from the ARB at the highest doses of ACE inhibitor. Typical of all of these analyses, the relative benefit of the ARB among those taking the highest doses of ACE inhibitor was comparable to those taking average doses.

As confirmed by Dr. Pfeffer, “It didn’t matter. The benefit of candesartan was incremental to that of the ACE inhibitor, regardless of what dose they were on.” He added that the data were compelling to both the investigators and the regulatory authorities in the US. On the basis of these data, the FDA, which had already approved the ARB for reduction of death and hospitalization in patients with heart failure, permitted the labelling to be changed to reflect its added effect on these outcomes when used with an ACE inhibitor.

New Canadian data appear to provide insight into the added effects of an ARB and an ACE inhibitor. In a placebo-controlled study that recruited 80 heart failure patients at four centres in Quebec and Ontario, several markers of inflammation and glucose regulation were evaluated in the presence or absence of an ARB. All patients were on an ACE inhibitor and 94% of patients were also taking a beta blocker. Typical of a heart failure population, 23% of the patients had diabetes and another 24% had glucose intolerance. Blood samples were evaluated for C-reactive protein (CRP), B-type natriuretic peptide (BNP), glucose levels and insulin levels. The change in fasting insulin resistance index (FIRI) was also calculated.

“These data help us evaluate whether there is room to improve outcome in a patient population that is already on an aggressive treatment regimen,” noted Dr. Michel White, Montreal Heart Institute, and Associate Professor of Medicine, Université de Montréal, Quebec. This study, which placed a much higher proportion of patients on beta blockers and other components of modern heart failure regimens than CHARM, “provides some mechanistic data that may explain the reduction in clinical events with dual angiotensin-II suppression in CHARM,” Dr. White told delegates.

Changes in Metabolism Monitored over Six Months

The average age of patients in this study was 62.5 years. While the average LVEF was 27.1%, 57.5% of patients were in NYHA class II heart failure and 41.3% were in class III. The patients were randomized to be titrated to 32 mg candesartan or to placebo and were then followed for six months. All analyses were conducted double-blind.

At the end of six months, BNP, a cardiac neurohormone that indicates worsening heart failure, increased by 8% (1218 vs. 1126 ng/L) relative to baseline in the placebo group but fell 11% (1644 vs. 1844 ng/L) in the active treatment group (P<0.05 for the ARB vs. placebo). Similarly, CRP increased 32% (7.58 vs. 5.70 mg/L) in the placebo group but fell 23% (5.30 vs. 6.90 mg/L) in the active treatment group (P<0.05). While blood glucose levels climbed slightly on placebo (8.16 vs. 7.88 mmol/L), they fell 17% (7.52 vs. 9.10 mmol/L) in the ARB group (P<0.05). Insulin levels were basically unchanged in the placebo group (156 vs. 147 pmol/L) but they climbed substantially in the active treatment group (274 vs. 191 pmol/L; 43%). As a result, although FIRI units climbed from 6.68 to 8.12 (26%) in the placebo group, they fell by nearly half (6.21 vs. 12.1, 49%) in the active treatment group.

The relative improvements were not observed in all patients on the ARB, but severity of heart failure varied widely in the study population. Although Dr. White suggested that additional studies are needed to compare responders and non-responders, he emphasized that the overall data are “supportive of added effects when an ARB and an ACE inhibitor are used together” in heart failure. In addition, the data support that these added effects may involve multiple systems, including mediators of inflammation and factors involved in glucose metabolism, particularly insulin availability. According to Dr. White, there are a number of explanations for the increased levels in insulin, including improved blood flow to the pancreas, “but the data say that there is something there,” and that these effects may at least partially explain the improvements in outcome in CHARM.

Focus on Adiponectin Levels

In another study, representing a collaboration between investigators at Gachon Medical School, Incheon, South Korea, and the U.S. National Institutes of Health, Bethesda, Maryland, an ARB and an ACE inhibitor demonstrated an increase in adiponectin levels relative to either an ARB or an ACE inhibitor alone. Adiponectin is a fat-derived hormone that appears to be an important mediator of glucose uptake, weight gain and other critical metabolic processes. Although this study was not conducted in heart failure patients, it may provide insight about pathogenic processes that appear to begin at the earliest stages of hypertension and other signs of abnormal vascular function.

“It may be important to address the controversy about whether ARBs and ACE inhibitors can provide additive effects even before patients evolve to heart failure,” suggested Dr. Seung Hwan Han, Gachon Medical School. He indicated that if these agents have additive benefit, it is likely to be detectable at early stages due to the evidence that RAS activation drives many early events, including hypertension.

In this randomized, double-blind, crossover study, 34 hypertensive patients were evaluated over three two-month study periods separated by two-month washout periods. The three study regimens were ramipril 10 mg plus placebo, candesartan 16 mg plus placebo, and ramipril 10 mg plus candesartan 16 mg. In addition to adiponectin levels, patients were evaluated for changes in flow-mediated dilation, in plasma insulin levels and changes and in insulin sensitivity using the Quantitative Insulin Sensitivity Check Index (QUICKI ) method.

Dr. Han reported, “Ramipril alone, candesartan alone, and ramipril plus candesartan increased adiponectin levels, but the greater increase on the combination was statistically significant [P=0.02] relative to either agent alone.” Similarly, all three arms improved flow-mediated dilations, but the advantage of the combination over either active monotherapy was substantial and highly statistically significant (P<0.001). However, “only the combined therapy significantly increased insulin sensitivity as determined by QUICKI [P=0.002),” Dr. Han stressed. Moreover, there were significant correlations between adiponectin levels and changes in QUICKI (P=0.004) on the combination therapy.

He told delegates, “The combination of candesartan and ramipril provides additive effects for improvements in metabolism and markers of vascular function.” Although Dr. Han acknowledged that it is unclear from these data whether the additive effects are generated from blockade of the effects of angiotensin II or from independent mechanisms of benefit, “the data predict the combination to be more effective for ameliorating metabolism and CV abnormalities than either treatment alone.”

Addressing Hyperkalemia

One concern raised by combining an ARB and an ACE inhibitor is the increased risk of hyperkalemia, a potential side effect from both classes of agents. An attempt to quantify this risk was the subject of another new analysis of data generated by the CHARM programme. As presented by Dr. Akshay S. Desai, Brigham and Women’s Hospital, the data confirm an association between the ARB and hyperkalemia and that the risk is increased by a number of factors, including simultaneous use of another RAS inhibitor, such as an ACE inhibitor or spironolactone. However, when a risk:benefit ratio is calculated, the data are supportive of an overall risk reduction from the use of an ARB.

“The data suggest that patients at increased risk for hyperkalemia should be monitored closely, but that the overall benefit outweighs the risk, which can be reduced substantially with appropriate surveillance,” Dr. Desai indicated.

In this data analysis of 7,599 patients participating in the CHARM trials programme, the risk of hyperkalemia climbed from 0.6% to 2.4% in patients receiving the ARB. This absolute difference of 1.8% was highly statistically significant (P<0.0001). The risk factors for hyperkalemia on the ARB were age 75 or older, the presence of diabetes, a baseline creatinine of at least 2.0 mg/dL, a baseline potassium of at least 5.0 mmol/L, and background use of ACE inhibitors or spironolactone.

The rate of serious adverse events associated with hyperkalemia was increased from 1.0% to 1.8%, an absolute difference that translated into seven events per 1,000 patients over 3.2 years. Over the same period, the ARB was associated with a reduction of 43 CV events. When patients were stratified by risk factors for hyperkalemia, such as use of an ACE inhibitor, older age or diabetes, the same relative reduction in CV events on the ARB was observed so that an overall favourable benefit:risk ratio persisted, despite the increased odds of developing hyperkalemia.

“The data suggest that all of the groups we identified as being at increased risk of hyperkalemia derive benefit from candesartan, but preserving the benefit in an individual patient depends on careful monitoring,” Dr. Desai told delegates.

Val-HeFT (Valsartan in Heart Failure Trial) was the first trial to suggest additive benefit in heart failure from a regimen that includes both an ACE inhibitor and an ARB. It associated the ARB valsartan with a 13.2% reduction (P=0.009) in the combined end point of heart failure mortality and morbidity. This study was conducted at an earlier point in the evolution of management when many patients did not receive beta blockers or other therapies now considered to be standard in mild to moderate heart failure. Consequently, the CHARM-Added trial provided a much firmer endorsement for the potential for additive effects. Due to the latest data, including those requested by the FDA, there is yet an additional basis on which to suggest that dual therapy may offer an opportunity to improve control of heart failure.

Summary

More detailed analyses of the CHARM-Added study have reinforced the conclusion that an ARB added to an ACE inhibitor provides protection against clinical events in patients with heart failure relative to an ACE inhibitor alone. Due to the different mechanisms by which these agents block angiotensin II, the added benefit may be due to improved inhibition of this neurohormone, which is a mediator of endothelial dysfunction, vascular hypertrophy and cardiac remodelling. However, the possibility that the additive benefits are due to unique effects on inflammatory and adverse metabolic processes is still being explored.