Does p-blocker titration failure reflect disease severity?

Several factors predict intolerance or nonresponse to (3-blockers in heart failure. Proposed markers of clinical deterioration are hypotension (systolic blood pressure <100 mm Hg) and hyponatremia (Na <137 mEq/L), on the grounds that massive neurohumoral activation fails to maintain salt and water and blood pressure homeostasis, with the result that further interference with this mechanism in the form of (3-blockade has negative effects. Paradoxically, some studies have shown that (3-blockers are less effective in patients with high plasma norepinephrine or aldosterone levels. Conversely, high baseline blood pressure, tachycardia, low plasma norepinephrine and high atrial natriuretic peptide (ANP) levels have been correlated with greater efficacy. Unfortunately, however, these parameters have a low positive predictive value and are unsuitable for differentiating between those patients who should, and should not, be offered (3-blocker therapy. A recent small study on the titration of bisoprolol in heart failure identified systolic blood pressure as the best predictor of dose titration failure in idiopathic dilated cardiomyopathy. Titration failure was independent of all standard measures of heart failure, such as left ventricular ejection fraction, peak V02, invasive hemodynamics, and neurohumoral activation. In addition, titration failure was associated with lower high-frequency power on spectral analysis of heart rate variability, suggesting decreased vagal tone, and increased low-frequency power, indicating increased sympathetic tone. Perkan et al found a decreasing probability of improvement in patients with a very high heart rate (>120 bpm), suggesting the existence of a limit value above which extreme tachycardia expresses not only neurohumoral activation, but also end-stage hemodynamic impairment, with a very low probability of reversibility.

Anthonio et al found no single predictor of intolerance on multivariate analysis, although univariate analysis showed strong associations with New York Heart Association (NYHA) class, age, diastolic pressure, and plasma urea. These parameters reflect greater vulnerability to the effects of cardiovascular drugs in general (advanced age), more severe disease (low diastolic pressure and high NYHA class), and multiorgan impairment (high urea).

Conversely, Macdonald et al found that although NYHA class IV patients were more likely than patients with milder disease to react adversely to initiation and dose titration, they were more likely to show symptomatic improvement in the long term. The class IV patients at most risk of adverse events were those who were hyponatremic on commencing carvedilol. Hyponatremia correlates closely with neurohumoral activation, in particular of the renin-angiotensin system, and is an independent predictor of mortality in severe heart failure. Hyponatremic patients are also more likely to be hypotensive and to have evidence of impaired peripheral and renal perfusion than class IV patients with normal serum sodium. Macdonald et al recommended admitting all class IV patients with hyponatremia or hypotension to hospital for the initiation of carvedilol.

In the recent CarvedilOl ProspEctive RaNdomlzed Cumulative Survival (COPERNICUS) study, carvedilol was well tolerated by clinically euvolemic patients with an ejection fraction <25% and symptomatic heart failure at rest or on minimal exertion. In fact, adverse effects in the carvedilol group forced fewer permanent treatment withdrawals than on placebo. To avoid an adverse short-term hemodynamic response, treatment should be initiated at a low dose, then gently Keywords P-blocker; intolerance; dose titration failure; neurohumoral activation; severe chronic heart failure [gallery ids=""]

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