Competing interest statement
Conflict of interest: the authors declare no potential conflict of interest.
Heart failure (HF) is a global pandemic affecting an estimated 26 million people worldwide and resulting in more than one million hospitalizations annually in both the United States and Europe.1,2 Nowadays HF is the leading cause of hospitalization and mortality, reaching 40% within five years following hospitalization.3 Survival estimates are 50% and 10% at 5 and 10 years after the diagnosis, respectively.4-6 In addiction, patients with HF are at high risk of repeated hospitalization, with a readmission rate of 25% of patients within 30 days from index hospitalization.7 Estimates of the prevalence of symptomatic HF in the general European population is similar to that in the United States, and ranges from 0.4% to 2%8 while the overall prevalence ranges from 1% to 12%.9 Despite recent advances in clinical approach, diagnosis and therapeutic management, the incidence and prevalence of HF are still increasing, owing to the better control of the disease and, largely, to the aging of the population.10 Due to the longer life expectancy, relative incidence of HF in women is approaching the one-half of HF cases.11
In Italy, it is estimated that 2% of the population is affected by HF, reaching the number of about 1,000,000 inhabitants (435,000 persons older than 65 years of age and 120,000 older than 80).12 HF is the leading cause of hospitalization over 65, thus it remains a growing public health problem. In the year 2012, the number of hospitalization for HF was around 200,000 events over a number of near 1,000,000 admissions for cardiovascular diseases, with an average length of stay of 9.1 days.13 Considering specifically the Campania region, the rate of hospitalization because of HF was of 343.3/100,000 inhabitants, representing the leading cause of hospitalization in subjects over 65 years old (1369/100,000 inhabitants).14,15 It is relatively common that patients admitted to hospital for any cause may suffer from HF as a coexisting medical problem, establishing a strong network of chronic diseases closely interrelated that greatly complicates diagnosis, management and outcome.16 As a consequence the HF is no longer considered as an isolated syndrome but part of a larger framework of multi-morbidity requiring a holistic approach in order to improve prognosis and quality of life.
The awareness of the epidemiological realities is a necessary datum for assessing the adequacy of local management but the available data on HF are not univocal, especially for the heterogeneity of the populations from which they are detected and managed [territory, Cardiology and Internal Medicine (IM) Units, and so on].17
The aim of this study was to evaluate the prevalence, clinical profile and relevance of comorbidities, the routine diagnostic and therapeutic work-up of chronic HF and to assess age and gender-related differences of the disease in patients coming from Campania region, admitted to IM Units.
Materials and Methods
The present study is a prospective, multicenter, observational study performed in 23 Internal Medicine wards representative of the regional setting of Campania. Diagnosis of HF was based on the guidelines of the European Society of Cardiology (ESC) 2012.18 For each patient the following data were collected at admission and recorded on an electronic format to allow assessment of provider-related differences in the clinical profile of the study population: day of hospitalization, gender, age, heart rate and rhythm, blood pressure, etiology of HF, New York Heart Association (NYHA) class, ejection fraction by echocardiography, previous hospitalizations up to twelve months before, comorbidities (see below), drug treatment including the use of new anticoagulant agents. Comorbidity was defined as the presence of at least one of the following: chronic obstructive pulmonary disease (COPD), diabetes mellitus, arterial hypertension, renal dysfunction, coronary artery disease, cerebral vascular diseases, liver diseases, malignancies. Measurement of left ventricular ejection fraction (LVEF) was used to estimate LV function. A LVEF >50% indicated preserved systolic function, as indicated in HF ESC guidelines.18
Continuous variables were summarized with mean and standard deviations and categorical percentages. Discrete variables were calculated by frequency percent and compared by the chi-square test. A P value <0.05 was considered as statistically significant. Statistical analysis was carried out by using SAS software (version 9.1; SAS Institute, Cary, NC, USA).
Nine hundred seventy-five patients admitted to IM wards with HF (19.5% of 5000 total admissions) between April 1 to June 30, 2014, were enrolled; 518 females (53%) and 457 males (47%). The baseline demographic and clinical features of studied patients are summarized in Table 1. Patients aged older than 70 were 741 (76%). Mean age [±standard deviation (SD)] was 76.9±9.9 (range 34-100). The mean age was higher in women than men, 79.3±9.0 versus 74.36±10.3 (P<0.05). Three hundred forty-nine patients (35.8%) had atrial fibrillation, with higher prevalence in women (41% vs 33.9%; P=0.02). With regard to underlying etiology of HF, coronary artery disease remained the leading cause without difference between men (62.3%) and women (52.5%); otherwise, the prevalence of non-ischemic heart failure resulted higher in women (47.4% vs 37.6%; P=0.002). NYHA class was indicated in 926 (94.9%) patient without significant gender difference observed in each subclass. 503 (51.5%) patients had LVEF measurement at the initial evaluation for enrollment; 170 patients (33.7%) presented with LVEF <40% without significant gender difference. Ninetythree patients (18.4%) had a severely reduced LVEF (<35%; 60 men and 33 women; P=0.0001); 87 patients (17.2%) presented with LVEF>50% with a higher prevalence of women (20.8% vs 13.7%; P<0.05). Three hundred eighty-seven patients (39.6%) had almost one hospital admission in the previous twelve months.
At the time of hospital admission, 8.6% of patients had one known disease other than HF, 24.7% had two comorbidities, and 64.8% more than two comorbidities (Figure 1). Arterial hypertension was present in 76.9% of patients with HF, with a significant higher prevalence in women (81.5%) than in men (71.8%), P=0.0001). Congestive heart failure (CHF) and COPD frequently coexist (49.4% of patients), with a significant gender-related difference (44.2% females vs 58.8% males - P<0.0001). Diabetes was found in 42% of patients. Chronic kidney disease (CKD) was present in 348 patients (35.7%), with higher prevalence in women (37.3% vs 33.9% - P=0.005). The most prescribed drugs were: β-blockers, angiotensin converting enzyme (ACE)-inhibitors and furosemide (Table 2). Out of the 170 patients with LVEF <40%, 120 (70.6%) received β-blockers. Interestingly, β-blockers were also used in 248 of the 482 (51.5%) patients with COPD, with a significantly higher frequency in men (139 vs 109, P=0.003). ACE-inhibitors were registered, in addition to a β-blocker, for all patients with EF <40% and in 172 of 348 (49.4%) patients with renal insufficiency. Loop diuretics were taken by 705 patients (72.3%) to control fluid retention and relieve congestive signs and symptoms, emerging as the preferred diuretic agents to use in most patients with advanced HF. As concerns patients with atrial fibrillation (n=342), 208 received an oral anticoagulant agent (181 warfarin and 27 a novel anticoagulant agent). Ninety patients with and 48 without atrial fibrillation took digoxin. Ivabradine was prescribed in 72 (7.3%) patients, 12 of them with a LVEF <35%.
Discussion and Conclusions
HF is an increasing health problem worldwide, with more than 21 million affected adults in the USA and Europe.19 The reasons for this pandemic include the increasing amount of causative factors that lead to an alteration in left ventricular structure and function such as coronary artery disease and hypertension, the improvements in medical therapies resulting in prolonged life expectancy and first and foremost the ageing of the population, since HF prevalence follows an exponential pattern rising with age. Data from the Kaiser Permanente System comparing the incidence of HF in 1970-1974 and 1990-1994 among people aged ≥65 years indicated that the age-adjusted incidence increased by 14% over time and was greater for older people and for men.20 In the Framingham Heart Study in the USA, it was estimated that in 1997 people aged over 65 years were 33 million (including approximately 7.9 million with age over 80 years-old) and that, by the year 2030, this number will rise to about 70 million (of which 18 million with age 80 years or older).21 This trend was also confirmed by the comparison between data of CONFINE study15 and of the previous TEMISTOCLE study,22 carried out in Italian Internal Medicine Units, depicting that from 2002 to 2008 the mean age of patients admitted for HF went up from 77 to 79 years. These features are confirmed in another recent Italian study on 770 patients with HF observed in Internal Medicine wards, showing a mean age of 82.5 years.23 Results of the present study agree with the above-mentioned data (mean age of 76.9 years, with 76% of patients older than 70 years). In a subgroup analysis in our whole series (Table 3), we observed several statistically significant age-differences as regards etiological factors, comorbidity and cardiac rhythm; all the same, some medications such as β-blockers, oral anticoagulant and double antiplatelet agents were significantly less frequent assumed in older patients. Various main factors may explain the high prevalence of HF in the elderly: progressive changes on an ongoing biological aging process, prolonged exposure to cardiovascular risk factors, comorbid conditions associated with ageing24 and the availability of effective treatments in patients with acute coronary syndromes extends survival increasing the incidence of HF.25
Various comorbidities usually coexist in elderly patients and contribute to the development of HF, end stage heart disease and death ant this negative prognostic impact of concomitant diseases has been documented in several studies.22-24,26 In the present survey we have observed that 64.9% patients had more than two chronic conditions, with a higher, but non-significant, prevalence in women. These results are quite similar to that of the above-mentioned Italian study.23 The most frequent comorbidities we registered were arterial hypertension (76.9%), COPD 49.4% and diabetes (42%). Previous epidemiological studies demonstrated similar high prevalence of diabetes in patients with HF, that is nearly four time greater than the prevalence of diabetes in the general population.27,28
As concerns etiological factors, the most common worldwide-described causes of HF [coronary artery disease (CAD) and arterial hypertension]29-31 were confirmed in the present study. Surveys on chronic HF in the community have shown that 40% to 50% of patients present with a LVEF ≥50%.32 In our study almost two/thirds of HF patients also presented with a preserved EF (>40%). These patients were mostly elderly and women, with a history of hypertension, and other co-morbidities.
In the present study significant gender differences were registered with regards to comorbidity, LVEF values and drugs assumed at admission (Table 4).
Many recent studies focused attention on the controversial issue of the role of gender on HF prognosis. Gender differences are recognized in the incidence, clinical presentation, and mortality associated with cardiovascular disease.33 Unfortunately, sex-specific diagnostic and treatment modalities have yet to gain similar attention which, in part, reflects incomplete understanding of physiological and cellular mechanisms contributing to gender differences in etiology of some cardiovascular diseases and failure to consider sex differences in pharmacokinetics and pharmacodynamics of drugs used to treat most cardiovascular diseases.34,35 Progress in understanding these mechanisms is slow due to the continued use of male animals in many types of experiments, lack of reporting of the sex and hormonal status of animals and cells used in mechanistic studies, and the absence of reporting of clinical trial results by gender.36-38
Gender differences in HF have been reported in relationship with the underlying physiology related to the sexual differences in hormonal status, metabolism and so on.39-41
We also looked at the cardiovascular treatment and we can make some supposition about physician adherence to evidence-based therapy. Despite the ACE-Is represent the first-line drugs in HF, at admission only 51% of patients were on therapy with ACE-Is while 20.5% of patients were on angiotensin receptor blockers (ARBs). The underuse of these drugs can be explained by the high prevalence of old age and CKD, as reported also in CONFINE study.15 In our study population, we did not observe statistically significant differences in the prescription of ACE-I in patients < or >70 years, while in patients with age >70 years we have seen even greater prescription of ARBs (22.2% vs 14.9%; P=0.02). One can speculate that the wider use in older patients of ARBs than ACE-I may be related with the better general tolerability of the former class of drugs. Furthermore, we found no statistically significant differences in prescribing ACE-I and ARBs in patients with and without CKD. Several studies showed that worsening of renal function in the setting of ACE-I initiation appears to represent a benign event that is not associated with a loss of benefit from continued ACE-I therapy42 and that prescription at the discharge of ACE-I or ARBs was associated with a significant modest reduction in all-cause mortality in older systolic heart failure patients with CKD including with more advanced CKD.43 The most prescribed drugs were loop diuretics coherently with the presence of congestion in the majority of subjects. An aldosterone receptor antagonist was used in 28.30% of patients with EF <35% and still in NYHA class II or III despite treatment with an ACE-I or an ARB and a β-blocker.
β-blockers were prescribed in 52.3% of patients, without difference between patients with and without COPD. It is interesting to observe that in Italian CHF-register (2003-2005)44 were reported a significant difference in β-blockers prescriptions between patients with and without COPD (34.4% vs 59.3% - P<0.0001); this occurrence may be in part related to the advent of selective β-blockers, too.45 Only 18.5% of patients with AF were receiving warfarin and 2.7% were under prescription of a novel anticoagulant and this represents a low percentage considering the registered CHA2DS2-VASC score in our series. But, as it is well-known, the compound of different parameters considered in CHA2DS2-VASC score are also items of HAS-BLED score; so, patients with high thromboembolic risk are often also at increased risk of bleeding and therefore there is greater fear in the prescription of oral anticoagulants in these elderly and frail patients.
In contrast with the previous Italian study we also considered the use of Ivabradine whose clinical benefits have been demonstrated both in patients with stable CAD with associated systolic left ventricular dysfunction or in patients with congestive HF.46
In our series, 387 (39.6%) patients had almost one hospitalization in the previous twelve months. This occurrence witnesses the complexity and fragility of the patient included in the present study. This high rate of re-admissions is related to the poor therapeutic compliance and suboptimal adherence to current guidelines we found in our population.
In conclusion, our data show that advanced age and the presence of multiple comorbidities characterize, in the hospital real life, patients with HF admitted to Internal Medicine wards in our Region. In addition, these data highlight some significant differences related to age range and to gender and that drug prescriptions on the territory are only in partial agreement with the standards outlined by the current guidelines.