Introduction

The prevalence of heart failure (HF) is 1%-2% among adult population in developed countries and 6-10% in the elderly groups. It is rising with an estimated 660,000 new cases each year1-5. In China, the HF prevalence increased to 29.1% from 16.9%6. The USA HF thirty-day mortality rate has decreased; however, the post-discharge mortality rate, re-admission, and admissions to nursing home facilities have increased. The economic burden of HF remains high7-17, 136-138.

A 2004 review has shown that HF disease management programs can reduce HF hospitalizations by 27%. However, HF hospitalization costs in the USA have increased by more than 175% during the last 25 years18-20. Incomplete implementation of trial methodology, inadequate patient education, absence of trained staff for follow-up monitoring, non-access to specialized HF clinics, application of complex adaptive systems framework, or disease management programs are possible reasons for the continued high burden of HF21-29. In a systematic review of chronic HF guidelines from Europe, 56% were consensus-based and 28% were evidenced-based advisories30-36. Furthermore, guidelines recommendations do not highlight the significant contribution of BDT. The concern is the lack of a statement describing that the Class I-A recommended IDT is in fact an ADT to the BDT44-65.

Objectives

To determine the survival and hospitalization event free rate in the BDT and IDT groups and to compute for the ADT survival and hospitalization event free rates.

Methodology

The chronic HF trials published by the 2005, 2009, and 2013 American Heart Association/American College of Cardiology (AHA/ACC), the 2006 Heart Failure Society of America (HFSA), and the 2005, 2008, and 2012 European Society of Cardiology (ESC) were reviewed, summarized, collated, and compared with the guidelines’ class I-A recommendations38-45. Other chronic HF studies and guidelines were reviewed for comparison46-47, 91-96.

BDT refers to the background HF (‘start’) medications used as placebo in the trial. IDT refers to the experimental (‘end’) drug used in the trial and is the guidelines’ suggested first line HF drug therapy. The add-on HF drug therapy or ADT survival and hospitalization event free rate is the absolute value of the difference between the BDT and the IDT rates. The natural HF survival rate of 38% is assumed based on published literature for the time period107.

Results

Table 1. Comparison of the 2005, 2009, and 2013 AHA/ACC, HFSA, as well as the 2005, 2008, and 2012 European Society of Cardiology Chronic HF Guidelines Recommendations on Drug Therapy.
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In summary, the chronic HF guidelines recommend the following:

  1. (1)

    ACE i can be given as a routine IDT for systolic dysfunction;

  2. (2)

    ARB is an alternative to ACEi for intolerant symptomatic HF patients;

  3. (3)

    BB is used in all stable patients with systolic dysfunction and chronic HF in addition to ACEI, digitalis, and diuretics;

  4. (4)

    Diuretics is recognized as BDT but HFSA recommends its optional use for symptomatic HF;

  5. (5)

    Aldosterone antagonists (MRA) are add-on to ACEI, BB, digitalis, and diuretics;

  6. (6)

    Digitalis “can be beneficial” as an add-on option in HF in sinus rhythm36-48

Table 2. Survival Rates in the Baseline HF drug therapy (BDT), Initial HF drug therapy (IDT) and Add on HF drug therapy (ADT) Groups in the HF Studies Used in the Reviewed HF Clinical Practice Guidelines.
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In summary, the reviewed HF studies showed the following:

  1. (1)

    The proportion of HF studies with BDT: 79%-100%

  2. (2)

    The Survival benefit of BDT group: 46%-89%

  3. (3)

    The Survival benefit of IDT group: 61%-92.8%

  4. (4)

    The Survival benefit of ADT group: 0.4%-15%.

Table 3. Proportions of Hospitalization and Computed Hospitalization Free Events in the Baseline HF drug therapy (BDT), Initial HF drug therapy (IDT), and Add on HF drug therapy (ADT) Groups in the HF Studies Used in the Reviewed HF Clinical Practice Guidelines
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In summary:

  1. (1)

    The HF hospitalization free event rate of BDT group: 47.1% to 85.3%

  2. (2)

    The HF hospitalization free event rate of IDT group: 61.8%-90%

  3. (3)

    The HF hospitalization-free event rate of ADT group: 4.6% to 14.7%

p diuretic withdrawal have adverse consequences175, 149.

education: a systematic review. Srisuk N1, Cameron J2, Ski CF3, Thompson DR.

Discussion

The chronic HF trials referenced in the chronic HF guidelines listed the use of numerous HF medications which comprised BDT45-48. The extent of the survival benefit of the BDT is 46%-89% and the IDT is 61%-92.8% with a calculated ADT survival of 0.4%-15%52, 64-65. The extent of the HF hospitalization free event rates of the BDT is 47.1%-85.3% and the IDT drug therapy is 61.8%-90% with a calculated ADT hospitalization free event rate of 4.6%-14.7%52, 64-65. Our review highlights a 6 times (89/15) survival rate in the BDT compared to the ADT and a 6 to 10 times (85.3/14.7 and 47.1/4.6) HF hospitalization- free event rate in the BDT compared to the ADT.

HF Survival and Hospitalization

Hospitalization marks a fundamental change in the natural history of HF. Three-fourths of all HF hospitalizations are due to symptom exacerbation with one-half of hospitalized HF patients experiencing readmissions within 6 months. Preventing HF hospitalization and re-hospitalization is important to improve patient outcomes and curb health care costs67, 68.

Avoidance of hospital admission can be equivalent to prolonging quality of life61-71.

Repeat HF hospitalization ranged from 22.7% in Latin America and 43.9% in North America143-144. Two-thirds of patients hospitalized for acute decompensated chronic heart failure have already survived a known history of heart failure.145-146. In the OPTIMIZE-HF Registry, rates of re-hospitalization were 30% post discharge173-174. In the EVEREST trial, 40% of post discharge deaths were from HF173-174. A prior history of HF decompensation or hospitalization identifies patients who are particularly at high risk of recurrent events147-148. Is HF re-hospitalization associated with ADT with or without BDT?

Baseline HF Drug Therapy

Withdrawal effect: A meta-analysis of loop diuretics in HF found a statistically significant survival benefit on top of baseline HF therapy74. Studies have showed that ACEi or digoxin use lowered mortality (OR 0.24); reduced worsening HF (OR 0.07), and improved exercise capacity. (OR 0.72)72-75. The PROVED and RADIANCE showed worsening HF occurred at 4.7% (digoxin, ACEi and diuretic therapy); 25% (ACEi and diuretic therapy); and 39% on diuretic alone (76-83) after withdrawal. Thus, the combination of digoxin, ACEi, and loop diuretic are relevant as BDT. Digoxin and loop diuretic withdrawal have adverse consequences.175, 149.

Diuretic effect: Doubling the dose of diuretics among symptomatic HF patients on beta blockers, ACEi or ARB, spironolactone, and digoxin, led to significant loss of weight, improvement in symptoms, and an increase in 6-minute walk distance150-151. Is this a cardio-renal effect?

Digoxin use and level: Recent opinions say that “not enough data supports the use of digoxin with current medications for chronic systolic heart failure like betablocker, spironolactone, and ACEI.” Thereby, the use of digoxin has not been emphasized in chronic heart failure treatment” guidelines152. There is evidence to show the contrary.

One study showed a 34% lower rate of all cause hospital admission in patients assigned to digoxin. This finding highlights an early beneficial effect of digoxin. 44% of patients enrolled in the DIG study used digoxin, those on digoxin maintained the treatment, while digoxin was stopped (without a washout period) among those assigned in the placebo153. Can this explain why the DIG study did not show all-cause mortality reduction since the placebo arm previously benefited from digoxin use?

Other studies have shown all-cause hospitalizations occurred in 5.4% vs 8.1% among chronic HF patients on the digoxin and placebo groups, respectively, (HR= 0.66). The 30-day cardiovascular hospitalization (HR 0.53; 0.38-0.72) and heart failure hospitalization (HR 0.40; 0.26-0.62) favored the digoxin group with similar trend in all-cause mortality (HR 0.55; 0.27-1.11). Younger patients were at lower risk of events and obtained similar benefits from digoxin154. Further, digoxin was associated with long-term improvement in kidney function and reduction in death or hospitalization157-159, 91-94, 100.

Digoxin reduces hospitalizations and improves symptoms when dosed to achieve low serum concentrations of 0.5-0.9 ng/ml (HR 0.81; 0.71–0.92)176. Further, studies have showed that lower serum digoxin concentration (0.5–0.9 ng/mL) was associated with reduced all-cause mortality (HR 0.77; 0.67–0.89), cardiovascular mortality (HR 0.83; 0.71–0.97), and heart failure mortality (HR 0.63; 0.49–0.82) (162). Current guidelines do not sufficiently emphasize the need to achieve low serum digoxin concentrations160-161. The DIG study is the only chronic HF study with serum digoxin level (SDL) determination.

Add on HF Drug Therapy

Total mortality or hospitalization, MI, and stroke did not differ between ARB and ACEi. Adverse effects resulted in increased withdrawals with combination ACEi and ARB101. Studies on BB therapy showed it improved survival, hospitalization, LV function, dyspnea, exercise tolerance time, NYHA FC, reduced death or readmission (OR=0.74), death or re-infarction (OR=0.77) or sudden death (OR=0.80)102, 103, 163, 164.

Short-term effects of BB withdrawal in acute decompensated heart failure have been reported177. BB withdrawal significantly increased risk of in-hospital mortality (RR 3.72;1.51 to 9.14), short-term mortality (RR 1.61;1.04 to 2.49), and combined short-term rehospitalization or death (RR1.59; 95% CI: 1.03 to 2.45). This data suggests BB should be continued in HF patients unless contraindicated165.

In CAD patients with heart failure and preserved systolic function, low-dose digoxin was significantly more effective than ivabradine166. Digitalis showed an OR for mortality of 0.98 (0.89-1.09), hospitalization of 0.68 (0.61-0.75), and clinical HF deterioration of 0.31 (0.21-0.43). Digoxin has no effect on long-term mortality; however, it reduced hospitalization and improved clinical status of symptomatic HF patients104, 105.

The Extrapolation

In the 21st century, the combination use of ACEI, ARB, BB, and aldosterone antagonist decreased hospitalizations and improved survival112-113. However, baseline HF drug therapy with digoxin and diuretics is a relevant concern66,48, 114.

If the recommended initial HF drug therapy survival rate is actually the add-on HF drug therapy recommended Class 1-A survival rate (computed as initial HF drug therapy survival rate MINUS the baseline HF drug therapy survival rate), then the computed add on HF drug therapy survival rate will be 0.4%-15%. Similarly, the computed add on HF drug therapy hospitalization free event rate will be 4.6%-14.7%.

The natural HF history survival in five years prior to current evidenced-based effective therapy is assumed to be 38%107. Therefore, given the derived baseline HF drug therapy survival rate of 46% to 89% MINUS 38% assumed natural HF survival rate, the extrapolated baseline HF drug therapy survival rate is 8% to 51% which is higher than the add-on HF drug therapy Class 1-A recommendation survival rate of 0.4%-15%.

Economic Impact of HF treatment

“The implementation of evidence-based therapy for HF treatment is not only clinically efficacious, but also economically attractive”97. To implement cost-effective strategies and contain the HF hospitalization epidemic, optimal identification of high-risk individuals and various multi-marker risk prediction schemes have to be developed98. Indeed, digoxin use gave a cost saving of >50% of several higher-risk HF patient subgroups99. Thus, combination HF therapy is still related to cost and clinical benefits.

Guidelines Adherence

In chronic HF cases and despite management by cardiologists, medical prescription differed substantially (> 50%) from guidelines’ recommendations167. The percentage of patients taking β-blockers was 38%; the percentage taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) was 32%168. Target doses for ACEi or ARB and BB were low at 40.3% and 28.9%, respectively169. Furthermore, the Heart Failure Adherence and Retention Trial has determined that 37% did not adhere to HF evidence-based guidelines170. In the China Outpatient HF Study, patients received target dose of ACEI/ARB (17.92%), BB (17.92%), respectively171. The low guideline directed medical therapy, usually IDT adherence, highlights the relevance of BDT

Limitations

The HF studies reviewed were limited to references and our analysis depended on the published trial data cited in the AHA/ACC, HFSA, and the ESC chronic HF guidelines without uniform “chronic HF definitions” although “unstable HF state” was excluded38, 39, 41-45. A later guideline review classified HF with typical HF symptoms, physical findings and definitive EF levels46.

The specific value of BDT and ADT to HF natural disease progression are unclear and hard to quantify at present. Whether digoxin added cost savings and reduced mortality and hospitalization is also speculative at this time. Other issues may affect the HF natural survival history thereby reducing the extrapolated survival benefits attributed to the BDT such as the following: (i) the contribution of renal failure, respiratory disease, anemia, cognitive impairment, falls and urinary incontinence118; (ii) the ‘real world’ acute HF exacerbations and re-admissions mortality of 8.2% that is independent of age, BP and creatinine levels119, 120; (iii) the 9.6% mortality and 19.4% re-hospitalization for CV causes at 90 days of HF admission121; (iv) the transition from preserved EF to reduced EF or a mixture of both122; (v) the higher cost of different HF diagnostic and management options123; (vi) the inability or poor utilization of HF biomarkers due to cost124; (vii) the adaptation of HF clinical pathways125; (viii) the presence of psycho-socioeconomic factors that are independent of HF development and leads to adverse outcomes126, (ix) the interactions between multiple drugs which affects acceptance and compliance127, and (x) family education at home to enhance patient self-care, boost dietary and treatment adherence182.

These undetermined and still unrecognized factors impact on the natural HF history and were not analyzed in this paper. Whether digoxin added cost savings and reduced mortality and hospitalizations can translate into substantial changes in the survival benefit attributable to baseline therapy is also speculative at this time.

Conclusion

The contribution of baseline HF drug therapy (BDT) is relevant in terms of the survival and hospitalization-free event rates compared to the HF class 1-A guidelines recommendations (IDT). Further, the proposed initial HF drug (‘end’) therapy (IDT) has possible synergistic effects to the baseline HF drug (‘start’) therapy (BDT) and is essentially the add on HF drug therapy (ADT) in our analysis. The polypharmacy HF treatment is a synergistic effect due to BDT and ADT.