Although ACE inhibitors are generally considered to have a favorable safety profile in heart failure, their use has been associated with first-dose hypotension, particularly in volume-depleted patients or those receiving an excessive initial dose. The in-hospital setting is ideal for dose titration, particularly in severely ill patients or those at risk of an adverse event. Patients with sodium levels <130 mmol/L usually receive the lowest dose. Although some clinicians may believe that sicker patients cannot tolerate higher doses, none of the commonest causes of intolerance (hypotension, renal failure, hyperkalemia) were predictive of low-dose therapy in recent studies. Thus patients are perhaps being treated with lower doses due to perceived rather than documented intolerance to high-dose therapy. For clinicians concerned about the possibility of hypotension, renal failure, or hyperkalemia, in-hospital titration provides the most controlled monitoring setting. Although titration may not be a sufficient reason for hospitalization in itself, it can run in parallel with other procedures and optimization of the patient's overall condition.
To maximize the likelihood that patients receive the correct dosage, once-daily drugs are preferable, being associated with both better compliance and higher dosages. Recent studies suggest that perindopril is particularly appropriate in heart failure: gradual onset of action, a low risk of first-dose hypotension, and no adverse blood pressure effects when started at low doses in normotensive patients.
Examining the relationships between (3-blocker use, 13-blocker dose, hospital admission for heart failure, and 1-year survival in a cohort of elderly survivors of myocardial infarction, Rochon et al found that b-blockers lowered subsequent admission for heart failure in patients with no previous history of heart failure, compared to those not receiving p-blockers. Low-dose therapy was associated with a lower rate of hospital admission for heart failure than high-dose therapy, and similar survival benefit. Thus patients receiving low-dose P-blockers and who are unable to tolerate higher doses should continue their therapy.
Recent studies suggest that over 90% of heart failure patients tolerate P-blockers. Those who initially tolerate low doses have an 80% chance of tolerating maximal doses. In the CarvedilOl ProspEctive RaNdomlsed Cumulative Survival (COPERNICUS) trial, there were fewer dropouts due to adverse effects or reasons other than death on carvedilol than on placebo.
Macdonald et al reported that adverse events were more frequent during initiation and dose titration in New York Heart Association (NYHA) functional class IV heart failure than in milder disease, but that there was a higher probability of long-term symptomatic improvement. Over half the adverse events occurred in the first 2 weeks of carvedilol therapy. The class IV patients most at risk were those with hyponatremia at initiation. Hyponatremic patients are more likely to be hypotensive, with evidence of impaired peripheral and renal perfusion, than those with normal serum sodium. Class IV patients thus require close observation during P-block-er initiation and titration when adverse event risk is maximal; indeed, according to Macdonald et al, those with hyponatremia or hypotension should be hospitalized specifically for this purpose. Long-term carvedilol was tolerated in 71% of their class IV patients. In those reacting adversely to initiation and titration, concomitant therapies were adjusted to allow the continuation of carvedilol. Exacerbated heart failure was generally treated with increased diuretics or nitrates. Uptitration of carvedilol was then postponed until complete resolution of the signs and symptoms of exacerbation, enabling one third of those with initial exacerbation of heart failure to remain on long-term carvedilol. Long-term outcome was as favorable in these patients as in those who tolerated carvedilol at the first attempt.
Krum et al found that carvedilol was well tolerated in everyday clinical practice. Multivariate analysis revealed no single predictor of poor tolerance, although the factors identified by univariate analysis included high NYHA class, advanced age, low diastolic pressure, and raised plasma urea. Anthonio et al found no association between failure of P-blocker titration and heart failure severity.
The message from all studies is that, for maximal p-blocker tolerability, it is mandatory to introduce treatment at low doses, followed by gentle escalation. Hypotension is best avoided by dosing with food, which halves the rate of absorption, and by separating administration from that of ACE inhibitors. Long-acting ACE inhibitors with a smoother hypotensive action are preferable where possible, eg, perindopril. A systolic blood pressure ^90 mm Hg is a warning to slow the uptitration of carvedilol and maintain the same dose for another 1 or 2 weeks, by which time the hypotension generally subsides. If the hypotension is symptomatic, or is impairing renal function, it may be necessary to withdraw other vasodilators, temporarily lower the dose of ACE inhibitor, or even lower the dose of carvedilol.
ACE inhibitor and (3-blocker combinations Flather et al conducted a prospective systematic overview of the individual patient data from five long-term randomized trials of ACE inhibition in left ventricular dysfunction or heart failure. In these trials the rates of (3-blocker use ranged from 17.8% in the Studies Of Left Ventricular Dysfunction (SOLVD) to 25.3% in the pooled Survival And Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and TRAn-dolapril Cardiac Evaluation (TRACE) trials. Overall P-blocker use in the five trials was 21.3%. Treatment benefits on all outcomes were independent of p-blocker use.
Since the vast majority of patients enrolled in heart failure trials are also treated with ACE inhibitors, the effects of p-blockers are largely additive: in COPERNICUS, 97% of patients were receiving an ACE inhibitor or angiotensin II receptor blocker; in the MEtoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF), the figure was 95% (ACE inhibitors: 90%); and in the Cardiac Insufficiency Bisoprolol Study (CIBIS), 96% were taking ACE inhibitors.
Berger et al retrospectively stratified heart transplantation candidates into those receiving P-blockers + ACE inhibitors (group A), ACE inhibitors (group B), and ACE inhibitors + intravenous support (group C). Overall, as many as 40% of these severely ill patients tolerated P-blockers on the top of maximally uptitrated ACE-
inhibitor therapy; 42% received optimized ACE-inhibitor therapy, but the mortality rate was relatively high (27%). Mortality was significantly lower in group A compared with group B due to a lower sudden-death rate. All event rates differed significantly between groups A and C. Total mortality was similar in groups B and C. However, urgent transplantation was more frequent in group C than in group B. The data suggest that it is most useful to add a p-blocker to ACE-inhibitor therapy in transplantation referrals, even if in patients tolerating this treatment transplantation does not seem to provide additional short-term (2-year) survival benefit.
In post-myocardial infarction studies, P-blockers have prevented recurrence, while the recent Heart Outcomes Prevention Evaluation (HOPE) study gave credence to the previously retrospective claims that ACE inhibitors are effective in preventing myocardial infarction. In contrast to the ACE inhibitor studies, the recent CIBIS-II and MERIT found few infarcts in their populations. Sudden death is common and decreased by p-blockers. As shown by data from the ATLAS and AIRE studies, ischemic events and arrhythmias may contribute not just to sudden death, but also to progression of failure.
A dose-response relationship was observed between higher doses and lower mortality in a cohort of elderly patients with heart failure and systolic dysfunction. In this analysis a non-statistically significant trend suggested that patients on target ACE-inhibitor doses were also more likely to be treated with P-blockers. It is plausible that patients on the target ACE-inhibitor dose had a trend toward lower mortality because they were treated with both ACE inhibitors and P-blockers, and that treatment with both drugs is strongly associated with clinical outcome. Titrating the ACE inhibitor to target may prevent some patients from receiving P-blocker therapy because of a higher incidence of adverse effects, whether perceived or actual. More clinical trial data are needed to determine the best approach to treating such patients.
As a part of the US Carvedilol Heart Failure Trials Program, a subanalysis was undertaken to determine whether NYHA class II-IV patients with a left ventricular ejection <35% whose background therapy did not include ACE inhibition experienced the same benefit as those receiving ACE inhibitors. Patients who could not tolerate ACE inhibitors had a similar decrease in mortality risk and a similar increase in ejection fraction. The frequency of adverse events did not differ between the two subgroups, with the exception of more frequent hypotension in the concomitant users of ACE-inhibitor therapy. Thus, in this small study, improvements in survival and ejection fraction associated with carvedilol treatment were observed to be similar in patients not receiving ACE inhibitors, accompanied by a lower frequency of vasodilator symptoms.
drug; ACEI; p-blocker; dosage; tolerability; optimization; advanced heart failure; combination therapy