The December lecture series in Zurich featured a presentation by PD Georg Noll, MD, on the treatment of chronic heart failure, in which he shared his practical clinical experience. The presentation by PD Jan Steffel, MD, provided information on the new indication of apixaban in stroke prevention in non-valvular atrial fibrillation; convincing study results are available.
According to PD Georg Noll, MD, Hirslanden, the diagnosis of heart failure has a similar prognosis for patients as a malignant tumor: “30% of hospitalized heart failure patients are given a prognosis of death.” In principle, therapy is increasingly intensified during the course to avoid hospitalization, but it is also a matter here of people’s quality of life, which should be maintained as far as possible.
The neurohumoral mechanisms of heart failure resemble a vicious circle: the body has no specific response to myocardial damage, which is at the beginning of the chain, but reacts just as it does to a lack of blood flow. “The body’s compensatory systems are correlated with the severity of heart failure: The more systems are activated, such as the renin-angiotensin-aldosterone system (RAAS) or the sympathetic nervous system, the worse the prognosis for the patient,” Dr. Noll made clear.
Diagnostic clarification and adequate treatment of heart failure
The diagnostic algorithm for heart failure (Fig. 1) is primarily intended for hospitals, but the general practitioner can also use the scheme to derive a valuable diagnostic strategy.
Pharmacotherapy is started with an ACE inhibitor. If this is tolerated, a consecutive treatment escalation provides for beta-blockers, then an aldosterone antagonist, and if the heart rate is >70 bpm, ivabradine. However, if the ACE inhibitor is not tolerated, the treating physician must switch to an AT1 receptor antagonist and then top up with beta blocker, aldosterone antagonist and ivabradine (if the heart rate with sinus rhythm is >70 bpm). “In addition to standard therapy, symptomatic treatment is essential, as otherwise the quality of life is reduced and the dreaded hospitalization occurs more quickly; this must be avoided,” recommends Dr. Noll. Symptomatic treatment includes diuretics as well as digitalis, nitrates, and ferric carboxymaltose.
Fortunately, study results are implemented quickly and successfully. This can be seen in the example of the RALES study [2]: After the online publication of the study results in 1999, the prescription rate for spironolactone, a potassium-sparing diuretic, increased in the same year, leading to a reduction in hospitalization rates. With eplerenone (Inspra
®
) is a selective aldosterone receptor antagonist (SARA) that is given in addition to standard therapy for chronic heart failure. The related chemical structure of the two drugs is intended to preserve the benefits of spironolactone on the one hand, but limit the side effects on the other. The results of the EPHESUS trial confirmed a significant reduction in mortality and morbidity in patients with severe heart failure from eplerenone versus placebo [3]. After just one month, the patient population studied in the eplerenone group showed a 32% reduction in cardiovascular mortality risk. After 30 months, the reduction in the relative risk rate for cardiovascular death or hospitalization was -13%, and for sudden death there was even a minus of 21%.
In the EMPHASIS trial, eplerenone, compared with placebo, showed a reduction in death from cardiovascular causes and reduction in hospitalization from heart failure [4]. The patient population studied was systolic heart failure patients with mild symptoms; standard treatment consisted of ACE inhibitors/angiotensin II receptor, beta-blockers, and loop diuretics. The study was terminated early for efficacy reasons. The eplerenone group showed a highly significant 7.6% absolute reduction in events in the primary endpoint of cardiovascular death and hospitalization for heart failure compared with placebo (18.3 vs. 25.9%; p<0.001). “This means that to prevent one event, we only need to treat about twelve patients. All-cause mortality was also significantly lower by 3% in the eplerenone-treated group. Further, the hospitalization rate due to heart failure decreased by 6.4%, this result is also highly significant. In my opinion, hospitalization in particular is an important factor, since it also relates to impaired quality of life. Overall, the data are very impressive and the subgroup analysis is also reassuring, as the results across all subgroups are consistent with the overall results. Overall, we see the positive results also confirmed in everyday practice,” is Dr. Noll’s assessment.
In terms of side effects, the results were comparable to placebo, but potassium levels should be monitored closely. Dr. Noll recommends an initial check and a recheck after one week.
New approval convinces with study results in VHF
“Atrial fibrillation (VHF) is almost an epidemic, as we will see a steep increase in prevalence over the next few years with the aging of the population and increasing risk factors,” said PD Jan Steffel, MD, Zurich, on the importance of the disease. It is also important to note in this regard that clots are often larger when they form in the atrial tube due to atrial fibrillation. This is because the consequences of a stroke are also much more severe than is the case with strokes caused in other ways.
“It is also critical to note that the fivefold increased risk of stroke exists for patients with VHF, regardless of whether the AF is symptomatic or not,” Dr. Steffel added. Stroke prevention with vitamin K antagonists, although effective, brings some pitfalls and difficulties. Monitoring blood coagulation is not only time-consuming, but the measurement results also show a large variance – depending on what was eaten and when the drug was administered. Further, Dr. Steffel noted that even within the ideal INR range of 2-3, the risk of cerebral hemorrhage is significantly increased in anticoagulated patients. Below this value, protection against stroke is only suboptimal, while INR values above 3 are associated with a greatly increased risk of bleeding. Another problem is the long half-life of vitamin K antagonists, which complicates and slows down the discontinuation and initiation of therapy and thus regularly poses great challenges to the treating physicians in hospitals, especially during emergency operations and interventions.
The new oral anticoagulants (NOAKs) were developed to address these problems. A NOAK with a new indication is apixaban (Eliquis®), an oral, direct Factor Xa inhibitor, which is now also approved for the prophylaxis of stroke and systemic embolism in adult patients with non-valvular VCF. Apixaban has good bioavailability (approx. 52%), an onset of action after just 3 – 4 hours and a half-life of approx. 12 hours, “which helps us enormously with interventions such as those that are often necessary spontaneously in elderly patients in hospitals,” says Dr. Steffel on the practical relevance. Another advantage of apixaban is that only one-third is broken down by the kidneys, making it suitable for patients with mild to moderate renal insufficiency.
Clinical data also show compelling results: The Phase III ARISTOTLE, efficacy superiority-focused trial demonstrated a significant risk reduction of stroke or systemic embolism of 21% in patients with VCF and at least one additional risk factor for stroke compared to warfarin (p=0.01) Severe bleeding was reduced by 31% (p<0.001), and all-cause mortality was also reduced by 11% (p=0.047) in the apixaban-treated patient group [5]. In addition, the results found were consistent across relevant subgroups and the number of discontinuing study participants was lower than in the warfarin group, supporting the safety profile of apixaban. “A very interesting finding is that diabetics on apixaban have significantly fewer major bleeding events. However, the significance of this finding is still unclear and requires further investigation,” Dr. Steffel offered an assessment.
AVERROES, also a phase III trial, evaluated the efficacy and tolerability of apixaban versus acetylsalicylic acid (ASA) in a patient population not suitable for therapy with VKA [6]. Patients benefited from a 55% lower risk of stroke or systemic embolism with apixaban. Overall, the risk of stroke was reduced by 54%, and the risk of ischemic stroke was reduced by as much as 63%. At the same time, bleeding rates were comparable in the treated groups. As in ARISTOTLE, AVERROES also showed a significantly lower dropout rate (17.9%) of study participants compared with the ASS group (20.5%).
“In summary, we can speak of very good results here. The new approval offers another alternative for treating physicians and is also a good option with regard to patients with impaired kidney function.”
Source: Media Roundtable, Thursday, November 28, 2013, Zurich
Literature:
- Heart Failure Working Group SGK, SAeZ 2003.
- Juurlink D, et al: Rates of hyperkalemia after Publication of the Randomized Aldactone Evaluation Study N Engl J Med 2004; 351: 543-551.
- Pitt B, et al: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348(14): 1309-1321.
- Zannad F, et al: Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1): 11-21.
- Granger CB, et al: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
- Connolly SJ, et al: Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 3: 806-817.
CARDIOVASC 2014; 13(2): 43-46
