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Journal of Clinical Medicine Research

Original Article

Volume 9, Number 6, June 2017, pages 488-498

Phosphodiesterase-5 Inhibitors Improve Clinical Outcomes, Exercise Capacity and Pulmonary Hemodynamics in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction: A Meta-Analysis

The cardinal symptom of heart failure, i.e., the dyspnea, is largely attributable to pulmonary hypertension (PH) and congestion in the pulmonary vasculature [1]. So it is crucial to emphasize the very important role that PH plays in causing the symptoms and the clinical picture of heart failure either right-sided or left-sided or biventricular. PH associated with left heart disease (PH-LHD) coincides with the group 2 of the most recent International Classification of the Pulmonary Hypertension [2]. The favorable effects of phosphodiesterase-5 (PDE5) inhibitors, in particular sildenafil, in the treatment of PH are mainly attributed to the action exerted on the pulmonary arteriolar - precapillary district (so-called “precapillary pulmonary selectivity” of PDE5 inhibitors) [3, 4]. In other words, the benefit of PDE5 inhibitors in treating heart failure may originate from their hemodynamic effect for the combined post- and pre-capillary PH (Cpc-PH), but not for the isolated post-capillary PH (Ipc-PH) [5].

In the present article, in order to evaluate the effects exercised by sildenafil or other PDE5 inhibitors on some functional, hemodynamic or clinical endpoints, a number of meta-analyses were separately conducted in patients with chronic heart failure with reduced (HFREF) or preserved (HFpEF) left ventricular ejection fraction (LVEF), respectively.

A systematic search using some related terms was conducted using the PubMed and Embase electronic archives. We limited our search to adults (> 18 years old) and to randomized controlled trials (RCTs). The study was performed according to the guidelines and recommendations expressed in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) [6] statement. Search terms firstly included “heart failure”, “sildenafil”, “vardenafil”, “tadalafil”, “avanafil”, “udenafil”, “phosphodiesterase 5 inhibitors”, “phosphodiesterase type 5 inhibitors”, “PDE5 inhibitors”, “cardiac dysfunction”, and “pulmonary hypertension”, variously combined by means of the Boolean operators “AND” and “OR”. Roots and variants of the search terms were also used. Studies had to be prospective RCTs. In each of the studies admitted to meta-analysis, a comparison had to be made between a group of CHF patients taking a PDE5 inhibitor and a second group assigned a placebo. Studies were incorporated in the meta-analysis provided that they had sufficient information about the explored hemodynamic and/or ergospirometric and/or clinical outcomes.

The included RCTs were assessed for the following outcomes: exercise capacity (peak VO₂ and 6-min walking distance (6MWD)), cardiac performance (LVEF, %), diastolic function (E/e’ ratio), and pulmonary resistance (mean pulmonary arterial pressure (mPAP, mm Hg), pulmonary arterial systolic pressure (PASP, mm Hg), and pulmonary vascular resistance (PVR, dyn·sec/cm⁵)). Clinical outcomes were assessed as all-cause death and hospitalization and adverse events.

All authors participated in determining the eligibility of candidate trials. The search included publications up to June 2016 and no lower date limit was applied. Titles and abstracts of all identified citations were reviewed independently by two authors (RDV and CA). Any candidate study was selected for further screening of the full text. In the event of a possible disagreement during data extraction, the intervention of a third reviewer (AC) was scheduled to solve any conflicting interpretation. Notably, it was decided that the studies selected for the meta-analysis should have included patients aged over 18 years. In addition, animal experimental studies as well as case reports of PDE5 inhibitor administration without a control group were eliminated from the meta-analysis. Similarly, all studies not written in English, duplicated studies, review articles, editorials and expert opinions were excluded.

The authors assessed the risk of bias for the recruited RCTs using the Cochrane Collaboration Risk of Bias Tool. The following risks of bias were evaluated: 1) random sequence generation; 2) allocation concealment; 3) blinding of participants and personnel; 4) blinding of outcome assessment; 5) incomplete outcome data; and 6) other bias.

In the case of dichotomous variables, e.g., the composite of “death and hospitalizations” or adverse events, the effect size was expressed as odds ratio (OR) with a 95% confidence interval (CI), using Mantel-Haenszel method as the weighting method. When the endpoint was a continuous variable, such as “change in mPAP” or “change in 6-min walking test”, the effect size was expressed as a difference in means (MD) with a 95% CI, using inverse variance as the weighting method. Due to the large variety of patients, the effect size was calculated using a random effects model, even in case no heterogeneity was found. Statistical heterogeneity across studies was tested using Cochran’s Q test and I² statistic (coefficient of variability due to inter-study variability). Statistical analyses were performed using RevMan 5.3 software (available from the Cochrane Collaboration; http//www.cochrane.org) and Stata version 10 (Stata Corp LP, College Station, TX, USA).

In our meta-analyses, 14 studies were incorporated on the whole (Fig. 1 and Tables 1 and 2). Among them, 13 were RCTs [3, 7-16, 18, 19] and one was a subgroup analysis [17]. Patients affected by HFREF included in our meta-analysis were 555. All of them were derived from the pooling of nine RCTs plus the afore-mentioned subanalysis study (Tables 1 and 2). Conversely, patients with HFpEF included in our meta-analysis were 373 on the whole. This value corresponds to the sum of the patients enrolled by four RCTs [8, 11, 14, 18], specifically aimed to explore the effects of PDE5 inhibitors in HFpEF.

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Figure 1. Flow diagram for meta-analysis according to PRISMA statement.

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Table 1. Baseline Features of Included RCTs

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Table 2. Different Impact of PDE5 Inhibitors According to Pulmonary Hemodynamics

Therefore, a total of 928 patients with chronic heart failure (CHF) were considered for the elaboration of the meta-analyses conducted in the course of our research. Among the included studies, 444 patients were assigned to sildenafil (with 443 patients assigned to placebo), and 21 patients were assigned to udenafil (with 20 patients assigned to placebo) (Tables 1 and 2).

Seven RCTs of HFREF [3, 7, 12, 13, 15, 16, 19] reported clinical outcomes, with five hospitalization events occurring in the PDE5 inhibitor arm and 17 occurring in the control arm. These results indicate a significant benefit conferred by PDE5 inhibitors against hospitalization (OR: 0.28; 95% CI: 0.10 - 0.74; P = 0.01; Fig. 2). Among the three RCTs concerning HFpEF that had included the endpoints of death and hospitalizations, one study [11] did not report any event, whereas the remaining two studies [14, 18] signaled 16 hospitalization events on the whole occurring in the PDE5 inhibitor arm and 18 occurring in the control arm (OR: 0.81; 95% CI: 0.41 - 1.63; P = 0.56; Fig. 2). During the follow-up period, five deaths were reported.

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Figure 2. Deaths/hospitalizations of HF.

The occurrence of adverse events in these studies did not significantly differ between the PDE5 inhibitor arm and the control arm (Fig. 3).

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Figure 3. Adverse events in patients with CHF.

The use of PDE5 inhibitor significantly improved exercise capacity in patients with HFREF (Figs. 4 and 5). In particular, among the six RCTs that had investigated the peak VO₂ in HFREF patients [3, 9-10, 12, 13, 16] this parameter was improved by the use of PDE5 inhibitors (difference in means (MD): 3.76; 95% CI: 3.27 - 4.25; P < 0.00001; Fig. 4). Similarly, based on the results of two studies [3, 7], in HFREF patients PDE5 inhibitor use yielded a significant betterment of 6MWD compared to placebo arm (MD: 22.7 m; 95% CI: 8.19 - 37.21; P = 0.002; Fig. 5). By contrast, in the RCTs of patients with HFpEF no benefit ensued from PDE5 inhibitor use regarding exercise capacity as measured by cardiopulmonary exercise test or 6 MWD (Figs. 4 and 5).

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Figure 4. Peak VO2 in CHF.

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Figure 5. The 6MWT in patients with CHF.

As regards the assessment of LVEF in patients with HFREF, based on the results of four studies [3, 10, 13, 16], the use of PDE5 inhibitor was associated with a significant increase in LVEF compared to placebo (MD: 4.30%; 95% CI: 2.18-6.42%; P < 0.0001; Fig. 6). By contrast, the use of PDE5 inhibitor for HFpEF patients resulted only in a non-significant tendency for increased LVEF (MD: 2.28%; 95% CI: -0.35% to 4.91%; P = 0.09; Fig. 6).

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Figure 6. LVEF in HFREF and HFPEF patients under treatment with PDE5i.

The use of PDE5 inhibitor in HFREF decreased mitral annular E/e’ ratio, but did not significantly affect this parameter in HFpEF (Fig. 7).

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Figure 7. E/e’ ratio in HFREF and HFPEF patients.

For patients with HFREF, PDE5 inhibitor caused a non-significant reduction in mPAP (MD: -6.73 mm Hg; 95% CI: -14.37 to 0.91; P = 0.08), while PASP was significantly reduced (MD: -11.52 mm Hg; 95% CI: -15.56 to -7.49; P < 0.00001) (Figs. 8 and 9).

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Figure 8. Pulmonary pressures in CHF patients.

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Figure 9. PVR during therapy with PDE5i.

The PDE5 inhibitor-mediated improvement in pulmonary hemodynamic parameters for patients with HFREF was concordant among the RCTs. The use of PDE5 inhibitor proved not to be associated with any significant improvement in pulmonary hemodynamics in patients with HFpEF (Figs. 8 and 9); however, the included RCTs showed very high heterogeneity (Fig. 8; I²: 99% for both mPAP and PASP in HFpEF patients).

The illustration of the various studies centered around the PDE5 inhibitor use in heart failure is far from simple. In addition, in order to explain the substantial failure of PDE5 inhibitors in HFpEF, you may need to refer to specific categories of hemodynamic profile regarding the pulmonary circulation. However, such an approach is only applicable to RCTs in which pulmonary catheterization was performed (five out 13; Tables 1 and 2).

Some aspects of this issue are highlighted below.

First, the PDE5 inhibitors have proven to improve the composite of death and hospitalizations compared to placebo in HFREF patients. This has to be emphasized because based on seven studies [3, 7, 12, 13, 15, 16, 19], it testifies the existence of an important protective role of PDE5 inhibitors against the risk of death and hospitalizations in HFREF patients. Among the studies incorporated in the meta-analysis, sildenafil was used in six studies and udenafil in one, with a total of 460 patients investigated about the endpoint “death and hospitalizations” (Fig. 2). It should be noted that a significant effect on this “hard” endpoint was not achieved by any of the individual studies considered (Notably, two studies were not evaluable for the absence of events, i.e., lack of death or hospitalization both in the arm of PDE5 inhibitor-treated patients and in the one of controls). Therefore, a statistically significant protective effect against death and/or hospitalizations (OR: 0.28; 95% CI: 0.10 - 0.74) was inferred in HFREF patients exclusively on the basis of the overall analysis of the aggregate data. However, this result has to be reported with the due emphasis because it is a novelty, and because it helps us to propose with the due caution the PDE5 inhibitors, in particular sildenafil, as candidate drugs ready to be inserted into the group of drugs (ACE inhibitors, beta blockers, and aldosterone receptor antagonists) that on the basis of substantial clinical evidence are currently regarded capable of providing significant benefit to patients with HFREF in terms of increased survival and/or survival free from hospitalizations. Obviously further studies, again in the form of RCTs, are warranted to corroborate and validate the results of this meta-analysis. As regards the functional parameters (exercise capacity and cardiac performance), a very important and solid evidence in favor of the use of PDE5 inhibitors has emerged from our meta-analysis. Indeed a functional betterment, ensuing from the administration of PDE5 inhibitor has been documented for the exercise capacity in HFREF patients. Indeed, based on six RCTs [3, 9, 10, 12, 13, 16] with a total of 206 HFREF patients randomized to PDE5 inhibitor or placebo, a substantial improvement in the peak VO₂ has been proven in the PDE5 inhibitor-treated patients. In particular, three studies have evidenced a significant increase in peak VO₂. Moreover, the analysis of aggregated data has confirmed the existence of a statistically significant meaning of the increase in peak VO₂ in the entire study population, related to the use of PDE5 inhibitor (weighted MD: 3.76; 95% CI: 3.27 - 4.25).

Among patients with HFREF, the 6MWT has been assessed only in two studies, whose overall evaluation by means of meta-analysis has evidenced an increase in functional capacity in the PDE5 inhibitor arm (Fig. 5). Even the LVEF was improved compared to placebo in HFREF patients taking therapy with sildenafil (Fig. 6).

In studies evaluating the measurements of the mPAP (two studies), PASP (four studies) and PVR (two studies), a significant reduction was consistently detected across the studies for each of these indexes in HFREF patients treated with PDE5 inhibitor compared to those taking placebo.

Different from the substantially favorable response of HFREF patients to PDE5 inhibitor administration, we did not observe any significant and consistent benefits conferred by PDE5 inhibitor treatment for patients with HFpEF. The reasons for this unsatisfactory response are at the moment unclear. In this regard, there are elements of significant perplexity in the fact that at least two studies [10, 16] would have documented an improvement in diastolic function index known as E/e’ ratio in patients with heart failure treated with sildenafil [10] or udenafil [16]. In addition, the molecular and biochemical pathways of sildenafil and related drugs, such as detected in experimental animals, appear to actually be compatible with the hypothesis of a favorable effect by PDE5 inhibitor on hemodynamic parameters and clinical outcomes of patients with HFpEF [20]. Conversely, with regard to the relatively low efficacy of PDE5 on hemodynamic and spiro-ergometric parameters, as well as on clinical outcomes in patients with HFpEF, as evidenced by some studies included in our meta-analysis [14, 18], this might depend on a possible predominance of the cases of Ipc-PH in these studies. This has been documented with certainty in the study by Hoendormis et al [14], in which a condition of Cpc-PH, regarded as a crucial element for the occurrence of a comprehensive and effective pharmacodynamic action of PDE5 inhibitor [5, 16] in the PH related to left heart disease, was present only in 12% of cases. The fact that the HFpEF patients investigated in these studies were to be ascribed predominantly to the Ipc-PH category might have played a crucial role in the generation of disappointing results.

Therefore, the thesis aimed to support a useful effect limited to the HFREF patients, due to an alleged lack of efficacy of the PDE5 inhibition in HFpEF patients should be regarded not adequately proven yet [21]. In fact, the highlighted difference about the effects reported in the two echographic phenotypes might depend on a lower frequency of Cpc-PH profile in HFpEF patients rather than on a real critical role of the type of left ventricular dysfunction (HFREF or HFpEF) in determining the clinical efficacy of the PDE5 inhibitors.

Therefore, in order to verify the possible causes of the unsatisfactory results of PDE5 ihibitors in HFpEF, further studies, conducted by recruiting HFpEF patients belonging to the Cpc-PH category, would be warranted.

The use of PDE5 inhibitors in patients with HFREF showed beneficial effects on pulmonary hemodynamics and exercise capacity. In addition, as regards the composite endpoint death/hospitalization, there was a significantly protective effect of PDE5 inhibitors, limited to the HFREF patients.

Conversely, the use of PDE5 inhibitors in patients with HFpEF showed disappointing results.

In fact, in the case of HFpEF patients, no significant improvement was achieved for each of the investigated endpoints (either functional, hemodynamic or clinical).

However, the hypothesis that the unfavorable results detected in HFpEF patients might have been caused by a not proper selection of the patient population (i.e., paucity of the cases of combined post- and pre-capillary PH in the studies conducted so far) should be taken into account. Thus, further studies with well-defined pulmonary hemodynamic profile, including an adequate number of HFpEF patients with Cpc-PH, would be warranted in order to better clarify the real therapeutic potential of PDE5 inhibitors even for treatment of HFpEF patients.

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