All-cause Hospitalization In Patients Research Articles

Long-term Outcomes of Disease Management in Chronic Obstructive Lung Disease: Results of VISN 23 Randomized Controlled Trial

PURPOSE: A Canadian disease management (DM) study demonstrated short- and long-term reductions in all-cause hospitalizations in patients with COPD even after active DM stopped (Eur Respir J 2005;26:853). Using a simplified COPD DM program, we previously demonstrated significant reductions in hospital admissions and urgent care visits during DM (Am J Respir Crit Care 2010;182:890). The purpose of this study was to determine the long-term outcomes of our patients who underwent DM.

Adherence to disease‐modifying antirheumatic drugs and the effects of exposure misclassification on the risk of hospital admission

To describe the effect of different exposure classification strategies for disease-modifying antirheumatic drugs (DMARDs) on drug-outcome associations. We studied the association between DMARD initiation and all-cause hospitalizations in patients with rheumatoid arthritis (RA), 1995-2005. Initiators of DMARDs and oral glucocorticoids were followed for < or =180 days. We compared 2 strategies for exposure classification: a persistent exposure required (PER) approach, in which followup stopped when the regimen changed; and a persistent exposure ignored (PEI) approach, in which followup continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference. We identified 28,906 episodes of medication initiation. In PER analyses, tumor necrosis factor alpha antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR] 1.36, 95% confidence interval [95% CI] 1.1-1.67). Glucocorticoids increased hospitalization risk (HR 1.29, 1.54, and 2.03 for low, medium, and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR 1.46, 95% CI 1.19-1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids and adherence to methotrexate was 59%. Compared with methotrexate initiation, leflunomide or glucocorticoid initiation consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence.

Low-dose digoxin and reduction in mortality and morbidity in heart failure

We thank Drs. van Veldhuisen and de Boer for their insightful comments regarding our recent report based on the Digitalis Investigation Group (DIG) trial [1]. We agree that digoxin should continue to play an important role in the management of heart failure [2, 3]. However, unfortunately digoxin continues to be underutilized in clinical practice [4]. This may be due to a lack of scientific discussion at national meetings, a lack of industry promotion, and an overemphasis on mortality over hospitalization as outcomes [5]. This latter reason is particularly ironic as hospitalization due to worsening heart failure, common in heart failure, is reduced by digoxin regardless of serum concentrations or daily dosages [6]. The introduction of beta-blockers since the DIG trial may also have contributed to the underuse of digoxin [5]. Most heart failure patients are older adults and we agree that beta-blockers are safe and well tolerated in elderly systolic heart failure patients [7–10]. In the SENIORS trials, nebivolol significantly reduced the primary combined end point of all-cause mortality or cardiovascular hospitalization in elderly heart failure patients, but had no significant effect on individual components of that composite end point [7]. In the MERIT-HF trial, metoprolol extended release was as effective in the elderly as in the younger heart failure patients [9]. However, heart failure patients enrolled in major beta-blocker trials were over a decade younger than typical heart failure patients seen in clinical practice [4, 10]. Mortality and morbidity in contemporary heart failure patients receiving beta-blockers and other neurohormonal antagonists remain high and many subsequent clinical trials using other interventions have failed to further improve outcomes. Yet, the role of digoxin in these patients is often questioned as the DIG trial was conducted before the beta-blocker era of heart failure therapy. Although this issue can only be definitively resolved with a large randomized clinical trial of digoxin in contemporary heart failure patients receiving beta-blockers, data from post-hoc analysis of beta-blocker trials suggest that digoxin and carvedilol may be equally effective in the presence or absence of each other. Digoxin reduced the combined endpoint of all-cause death or all-cause hospitalization in patients receiving carvedilol (relative risk {RR}, 0.64; 95% confidence interval {CI}, 0.52 to 0.79) and placebo (RR, 0.82; 95% CI, 0.71 to 0.99) [11]. Carvedilol, on the other hand, had similar effect on combined endpoint in patients receiving (RR, 0.63; 95% CI, 0.52 to 0.75) and not receiving (RR, 0.80; 95% CI, 0.64 to 1.00) digoxin [11]. A plausible explanation of this synergy may be that by reducing digoxin-induced serious arrhythmias, beta-blockers enhance the effectiveness of digoxin, and by providing inotropic support, digoxin improves the tolerability for beta-blockers. All major beta-blocker trials in heart failure excluded patients with diastolic heart failure, who constitute nearly half of all elderly heart failure patients. Data from the DIG ancillary trial suggest that digoxin may play a role in the management of diastolic heart failure [12]. The effects of digoxin in these patients were very similar to those of candesartan, the only other drug tested in diastolic heart failure in a large randomized clinical trial [5, 12]. Digoxin was better tolerated and patients receiving digoxin had fewer adverse effects than those receiving candesartan [5]. Digoxin is also inexpensive, an important consideration for millions of heart failure patients in the developing world, whose left ventricular ejection fraction often cannot be known. The safety and effectiveness of digoxin in elderly heart failure patients has been documented in a post-hoc analysis of the DIG trial [13]. Findings from that analysis suggest that the use of digoxin in low doses (≤0.125 mg/day) was a strong predictor of low serum concentrations, which was significantly associated with reduced mortality and hospitalization in these patients [13]. However, in frail elderly heart failure patients with impaired kidney function, even a lower daily dose (0.125 mg every other day) may be preferable [13]. For a definite resolution of the role of digoxin in contemporary heart failure patients, a second multicenter randomized clinical trial of digoxin is warranted. This trial should be designed to include equal representations of men and women, whites and non-whites, and systolic and diastolic heart failure patients. However, there may not be enthusiasm in the industry to fund such a trial. We therefore hope that public international funding would be made available to support a definitive trial of digoxin in contemporary heart failure in the greater public health interest.

How should subgroup analyses affect clinical practice? Insights from the Metoprolol Succinate Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF).

The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups. To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women). MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction < or =0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose. Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis. Overall, MERIT-HF demonstrated a 34% reduction in total mortality ( p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization ( p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% ( p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily. Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.

Pharmacoeconomics in heart failure: impact of drug and non-drug based treatment

Heart failure is a common and increasing problem associated with a high morbidity and mortality. The high morbidity of heart failure imposes the majority of costs of its treatment. Hospitalization among patients with heart failure is frequent, increasing, recurrent and often prolonged and constitutes about 65% of health spending on heart failure. A number of strategies can be envisaged to reduce recurrent heart failure hospitalization. ACE inhibitors (especially high-dose), beta-blockers, spironolactone and possibly digoxin, have all been shown to reduce substantially all-cause hospitalization in patients with heart failure in double-blind controlled trials. The most common single reason for re-admission is for worsening heart failure which may frequently be exacerbated by incomplete and unpredictable absorption of some diuretics. The loop diuretic, torasemide, because of its favourable pharmacokinetic and pharmacodynamic profile may be able to prevent worsening of underlying heart failure developing into a crisis, leading to hospitalization. Studies confirm that treatment with torasemide can reduce the rate of hospitalization due to worsening heart failure and is cost-effective, A stumbling block to progress that is often encountered is the unwillingness of budget holders to spend a small amount of money on better drugs and outpatient services in order to prevent hospitalization. This is exacerbated in many countries by a separate system for care of patients in and out of hospital.