The results of our study revealed that in patients hospitalized all over the country in the year 2013 due to exacerbation of HF those additionally treated with AA had 18% lower risk of all-cause death mortality and 15% lower risk of secondary endpoint (mortality or readmission) compared to the patients not treated with AA.
Compared to classic registry data, the patients in our study were 5 to 9 years older [10–17].
Balsam et al. analysed n = 1415 hospitalized patients from Polish cohorts of both ESC-HF Pilot and ESC-HF-LT registries [17]. The mean age was lower (69 yrs.) than in our cohort. Hypertension was diagnosed in 68.9%, CAD in 43.6%, AF in 43.6% pts, diabetes in 35.1%, CKD 20.9%, COPD 18.8% of patients. In the large american ADHERE registry the most common comorbid conditions were hypertension (73%), coronary artery disease (57%), and diabetes (44%) [13].
Despite the fact that only patients who purchased at least one of the classic drugs increasing survival were eligible for the study, in our cohort a lesser percentage of patients filled prescriptions for CV drugs comparing treatment at discharge in mentioned above Polish cohorts of European registries. While the difference regarding ACEi and ARB was approximately 10%, and for MRA approx 20 %, in case of BB, diuretics, digoxine, statins the percentage was twice smaller [17].
These differences may reflect the poor compliance and filling prescriptions among real-life HF patients.
Probably some drugs were not prescribed at the time of discharge from hospital, possibly due to contraindications (hypotension, bradycardia, renal failure).
Our cohort represents real life data and included exclusively patients with exacerbation of HF in contrast to registry studies that also included stable and outpatient HF patients and were conducted most often by selected centers of the tertiary level, often academic so probably selecting patients with lower age, smaller number of concomitant diseases and with better compliance.
The percentage of AA use in our men-only subgroup (8%) was similar to the frequency of BPE reported among U.S. Medicare beneficiaries with HF (6%) [9] suggesting that treatment of BPE not hypertension was the main indication for AA treatment.
Of n = 107 229 patients who were hospitalized for exacerbation of HF in the year 2013 but without hospital HF diagnosis in the previous year 10.3 % patients died during the index hospitalization and 4.9 % within 30 days after discharge, 4.3 % were readmitted within 30 days. The in-hospital mortality was 2–3 times higher than in registry studies [11], 13, 17].
Similarly to other registers that included acute HF patients, there was a high long-term mortality despite the fact that we excluded patients who died or were readmitted early [18, 19]. Also one-year mortality was 50% higher than reported in Polish cohorts of European registries [17].
On the other hand, patients who were not hospitalized with the diagnosis of heart failure during the previous year and who purchased at least one drug reducing the risk of death in HF within 30 days were enrolled, so the study group probably included more patients with de novo heart failure and cooperating well.
We decided to combine readmissions with total mortality as a secondary endpoint, since we have data on readmissions due to exacerbation of HF only but not total cardiovascular hospitalizations. Moreover high mortality in our cohort interferes with assessment of other endpoints.
Unlike randomized drug trials conducted in HF, our group was not selected in terms of HF severity, NYHA class, EF, etiology, renal function and other clinical parameters. Most of the randomized trials in HF have ruled out multiple coexisting chronic diseases, so the populations studied do not reflect well the patients treated in the hospital for worsening heart failure. The real-word data differs from randomised controlled trials (RCT) because of frequent exclusion of concomitant chronic conditions. In one analysis 83 % of RCT for heart failure excluded at least one chronic condition including CHD, hypertension, stroke, AF, COPD, depression or dementia [20].
The results of our study stays in contrast to the results of the ALLHAT study that disclosed nearly double the incidence of heart failure compared with chlorthalidone group in high risk hypertensive patients [3]. Although many authors explained the results of ALLHAT in doxazosin arm by the effect of neurohormonal activation from unopposed alpha receptor antagonism [21], others pointed to numerous limitations of the trial and issues needed to be addressed [22]. Systolic blood pressure was about 3 mm Hg higher in the doxazosin arm and increased incidence of heart failure in the doxazosin group was not accompanied by parallel increase in mortality. Moreover, the heart failure end point in ALLHAT was much higher than that observed in other trials of similarly high-risk patients and the curves for heart failure incidence in the doxazosin and chlorthalidone groups separated within weeks after randomization with little further separation thereafter. Therefore the treatment with doxazosin may rather have unmasked occult heart failure while diuretic treatment would have been more likely to maintain control of signs and symptoms of preexisting heart failure [22].
The results of the Matsui et al. study assessing the benefits of adding bed-time dose of doxazosin for controlling morning blood pressure and the left ventricular structure and function in hypertensive patients were unequivocal [23].
In the doxazosin group, an increase in the left ventricular diameter was only seen in patients who did not take diuretics throughout the study. Authors conclude that the prior use of diuretics can prevent the unfavorable effects of doxazosin on the left ventricular structure. These observations can explain the results of early studies with AA in HF.
On the other hand in a classical study comparing monotherapy with various 5 drugs in hypertensive men in the prazosin group there was no excess of oedema during more than one year follow-up, although the drug had also the highest rate of adverse effects leading to the termination of treatment [24].
In non-randomised analysis in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) that included almost 40 000 patient-years the addition of doxazosin to the hypertensive treatment resulted in BP lovering by approximately 12/7 mmHg with achieving target BP in one third of participants with no apparent excess of heart failure [25].
The observations regarding the use of AA in hypertnesive patients may not necessarily reflect well the use of these drugs in already treated HF.
In historical double blind comparison of captopril and prazosin in HF despite the maintained vasodilatation half of the 16 patients deteriorated after one month [26]. In our study, patients took (bought) at least one drug reducing mortality in heart failure. The study therefore tested the differences between adding AA as an additional drug to current therapy for heart failure, and did not compare AA with other classic drugs used in the treatment of HF.
The use of AA in a patient with HF in a situation where the drug is used to inhibit sympathetic activity and/or the RA system may not lead to excessive neurohormonal activation. The V-HeFT I trial revealed no differences in all-cause hospitalization between patients randomized to prazosin or hydralazine with isosorbide dinitrate or placebo in HF patients on background therapy of digitalis and diuretics [27].
The results of our study appear similar to the Jackevicius et al. study [7]. The authors performed the propensity score analysis of HF hospitalized in one institution from the year 2002 to 2015. Of 169 911 patients who were hospitalized in the period of interest 28% were on AA. The authors matched 35 715 pairs according to the AA treatment status using numerous covariants unfortunately with the exception of the most important as SBP and EF. The mean age of the matched group was lower (75 yrs) than in our study, and the usage of analysed drugs was higher than in our group with the exception of ACEi or ARB which was similar and MRA which was higher in our group. The treatment with AA was associated with lower 2-year all-cause mortality in the whole group (42.8% versus 46.5% (HR: 0.93; 95% CI: 0.91 to 0.94; P < 0.0001) and also in BB treated group (HR: 0.91; 95% CI: 0.89 to 0.92; P < 0.0001). Higher doses and nonselective AAs were also associated with lower mortality, regardless of BB treatment. These secondary analyses were performed in a very similar way, as the our. Authors conclude that AAs may be used safely in HF patients where clinically indicated.
Another example suggesting the benefits of adding AA to the treatment of HF is the COMET study (Carvedilol Or Metoprolol European Trial), that revealed a significant reduction in total and cardiovascular mortality with carvedilol compared with metoprolol [28].
Our study presents the typical limitations of a retrospective analysis of reimbursement data. However, the data were collected systematically and prospectively by a single insurer all over the country. Due to the limitations of the NHF database we were unable to assess many other important clinical parameters such as blood pressure, ejection fraction, laboratory tests (BNP or NTproBNP, plasma creatinine, natremia, haemoglobin) and concomitant diseases.
However we had data on duration of hospitalization, advanced HF (requiring treatment with positive inotropes or renal replacement therapy) and post discharge treatment. We assume that including these covariants into analysis partially substitutes controlling on important clinical parameters or concomitant diseases. Some of the studies mentioned in the above discussion also did not control results on crucial data such as SBP or EF due to incompleteness [7].
One can assume that the main indication for AA treatment in men was LUTS while in women poorly controlled hypertension. Therefore the men and women in our cohort may differ regarding both etiology and severity of HF. However the subgroup analysis in men only reflected the trends observed in the entire patient group.
Autopsies are rarely performed in Poland and a majority of deaths took place outside hospitals therefore we were unable to establish the cause of death.
A risk of potential errors or underreporting of diagnoses or procedures should also be taken into consideration.
Our all-over the country cohort analysis based on real world data revealed that in selected patients hospitalized due to HF exacerbation post discharge treatment with AA may be safe and beneficial. Since the inclusion/exclusion criteria we used the results of the study applied rather to the compliant patients without the highest risk of early post-discharge death or early readmission. The role of AA in HF warrants further research.