Implementing clinical trial results into clinical practice for patients with heart failure

Abstract

Today, it is widely accepted that patients with systolic congestive heart failure (HF) should be treated with a combination of drugs, including angiotensin-converting enzyme (ACE) inhibitors, blockers, aldosterone blockers, diuretics, and digoxin. Unfortunately, many patients with HF do not receive optimal therapy, despite the publication of numerous well-designed clinical trials. For example, ACE inhibitors were prescribed at discharge at a median rate of only 69% in Medicare beneficiaries admitted with a principal diagnosis of HF and a left ventricular ejection fraction of 0.40. 1 In a review of the rate of appropriate ACE inhibitor use (defined as the use of ACE inhibitors in patients with HF who do not have contraindications to their use, such as renal failure), Stratis Health (Minnesota’s Medicare Peer Review Organization) reported appropriate ACE inhibitor use at a median rate of 79% nationwide and at 81% in Minnesota. However, even when started appropriately, doses of prescribed ACE inhibitors are often substantially lower than the target doses used in the clinical trials that have established the utility of these medications. 2,3 As interest in neurohormonal antagonism with blockers in HF continues to increase, these same issues regarding utilization and dosing are re-emerging. Data on the current use of blockers for HF in the community are scant, but estimates of eligible patients with HF receiving blocker therapy have been as low as 5% to 15%. 4 Although data regarding use of blockers in patients with HF have yet to be evaluated systematically in the community, anecdotal experience suggests that, as with the ACE inhibitors, the dosages of these agents for patients with HF falls short of those evaluated and validated in clinical trials. This represents a limitation in the optimal utilization and implementation of ameliorating life-saving therapies for HF. Clinical trials have been indispensable in the evolution of HF therapy. However, the generalized application of their results to broader clinical practice must be done with an understanding of clinical trial design and the way in which that design should guide the application of clinical trial results. To be successful, randomized clinical trials ask specific questions about well-defined, relatively homogenous populations to maximize their internal validity (i.e., to successfully answer the particular question of the particular study). However, maximizing this internal validity can come at the cost of external validity (i.e., applicability to general clinical practice). External validity (or generalizability) is seldom addressed adequately in any single study because of the nature of clinical trials. Thus, although clinical trials have shown us what current optimal treatment should be, it can be difficult to apply their results to general clinical practice. This was recently illustrated in the Assessment of Treatment with Lisinopril and Survival (ATLAS) study. 5 In ATLAS, patients with symptomatic HF who received high doses (32.5 to 35 mg 4 times a day) of lisinopril had a significantly lower risk of all-cause mortality or hospitalization (for any reason, for cardiovascular causes, and for HF) than patients who received very low doses (2.5 to 5.0 mg 4 times a day). Only 20 patients needed to be treated at the higher dose before there was 1 less death or hospitalization for HF compared with patients receiving the very low dose of lisinopril. The fact that this trial did not evaluate medium lisinopril doses in the range that most patients actually take (10 to 20 mg 4 times a day) makes it difficult to generalize the trial results to community practice. Thus, it is important to help clinicians implement therapies validated in clinical trials in patients with similar clinical profiles using doses that approximate those that have been effective in the studies. To do otherwise limits the potential