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Effects of phosphodiesterase 5 inhibition on cardiovascular function in resistant hypertension: A systematic review (2021)
Amanda Sampaio Storch, Larissa Lírio Velasco, Antonio Claudio Lucas da Nobrega, Ronaldo Altenburg Odebrecht Curi Gismondi, Natalia Galito Rocha
ABSTRACT
Approximately 12–18% of hypertensive patients are diagnosed with resistant hypertension (RH). The risk of having worse cardiovascular outcomes is twice higher in those patients. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate complementary drug therapies to achieve blood pressure (BP) control. Previous studies have demonstrated that phosphodiesterase 5 (PDE-5) inhibitors improve hemodynamics and reduce BP on essential hypertension. So, the authors aimed to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of patients with RH. We searched MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry databases on May 15th, 2020 using pre-defined search terms. Two independent reviewers assessed and extracted data from clinical trials that evaluated the effect of PDE-5 inhibitors on BP. We have included five articles in this systematic review. Four of them developed a single-day protocol, while one has developed a 14-day study. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial function, but it was not a consensus. The side effects seemed to be limited and well-tolerated. In brief, our systematic review highlights the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Larger studies are still needed to determine whether the beneficial effects of PDE-5 inhibitors on RH would be maintained with chronic administration.
1. Introduction
Resistant hypertension (RH) is defined by resting blood pressure (BP) persistently above 140/90 mmHg despite treatment with three different antihypertensive agents (including diuretics) at the optimal dose [1]. RH is also characterized when BP control is achieved with four or more antihypertensive drugs [1]. Recent epidemiological trends estimate that the prevalence of RH is around 12–18% among patients with diagnosed hypertension [2]. The risk of having worse cardiovascular outcomes is twice higher in those patients when compared to essential hypertension [3]. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate alternative medication on their cardiovascular function.
Nitric oxide (NO) is the main endothelium-dependent vasodilator. NO disseminates to adjacent smooth muscle cells, leading to relaxation through guanosine triphosphate (GTP) conversion into cyclic guanosine monophosphate (cGMP) by guanylate cyclase enzyme [4]. The cGMP is degraded by phosphodiesterase 5 (PDE-5), widely expressed in whole body smooth muscles. Therefore, drugs that specifically inhibit PDE-5 increase the cGMP intracellular bioavailability and prolong its vasodilator effects [5]. In addition to the therapeutic effect on erectile dysfunction and pulmonary hypertension, several studies have shown that PDE-5 inhibitors improve BP and hemodynamics in essential hypertension [6,7].
Given the last decade's advances in the comprehension of RH pathophysiology and treatments, the authors intend to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of adults with RH. We believe that this systematic review can be relevant to guide clinician treatment choices and future research.
3.2. Blood pressure
3.3. Diastolic function
3.4. Endothelial dysfunction
3.5. Arterial wave reflection
3.6. Other hemodynamic variables
3.7. Plasma measurements
3.8. Side effects
4. Discussion
In this systematic review, we attempted to evaluate the effects of PDE-5 inhibitors on blood pressure and hemodynamics in this therapeutically challenging group of HR patients. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial dysfunction but they were not a consensus.
5. Limitations
Since five small, heterogeneous, and high-risk bias studies have been included in this systematic review, the evidence retrieved must be evaluated with caution. Four of them developed an acute protocol, but the experimental design was similar only in two articles. Furthermore, just one has developed a 14-day study of the effects of PDE-5 inhibitors in RH patients. For these reasons, it is difficult to draw firm conclusions regarding the impact of PDE-5 inhibitors on blood pressure and hemodynamics on RH. Nevertheless, RH consists of a very specific population with several challenges to enroll large numbers of participants, such as the high cardiovascular risk and a variety of associated comorbidities [1]. These peculiarities result in precluding safe withdrawal of medications and confounding interpretation of results, justifying studies with small sample sizes.
Another limitation is the possibility of publication bias. The failure to identify unpublished negative trials could lead to an overestimation of the effect of PDE-5 inhibitors on RH. However, to minimize publication bias, the search strategy included platforms that index ongoing clinical trials, congresses abstracts, academic papers (e.g., theses, dissertations, and monographs), among other publications. The authors also checked the references of all included articles and reviews retrieved by search terms.
6. Conclusion
Taking all data together, our systematic review suggests that PDE-5 inhibitors improve BP control, vascular hemodynamics, and diastolic dysfunction parameters. Our findings highlight the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Prolonged and larger studies are still needed to determine whether the beneficial cardiovascular effects of PDE-5 inhibitors on RH would be maintained with chronic administration. Future research should also focus on exploring the underlying molecular mechanisms that explain the hemodynamic benefits of PDE-5 inhibition in RH patients.
Amanda Sampaio Storch, Larissa Lírio Velasco, Antonio Claudio Lucas da Nobrega, Ronaldo Altenburg Odebrecht Curi Gismondi, Natalia Galito Rocha
ABSTRACT
Approximately 12–18% of hypertensive patients are diagnosed with resistant hypertension (RH). The risk of having worse cardiovascular outcomes is twice higher in those patients. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate complementary drug therapies to achieve blood pressure (BP) control. Previous studies have demonstrated that phosphodiesterase 5 (PDE-5) inhibitors improve hemodynamics and reduce BP on essential hypertension. So, the authors aimed to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of patients with RH. We searched MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry databases on May 15th, 2020 using pre-defined search terms. Two independent reviewers assessed and extracted data from clinical trials that evaluated the effect of PDE-5 inhibitors on BP. We have included five articles in this systematic review. Four of them developed a single-day protocol, while one has developed a 14-day study. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial function, but it was not a consensus. The side effects seemed to be limited and well-tolerated. In brief, our systematic review highlights the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Larger studies are still needed to determine whether the beneficial effects of PDE-5 inhibitors on RH would be maintained with chronic administration.
1. Introduction
Resistant hypertension (RH) is defined by resting blood pressure (BP) persistently above 140/90 mmHg despite treatment with three different antihypertensive agents (including diuretics) at the optimal dose [1]. RH is also characterized when BP control is achieved with four or more antihypertensive drugs [1]. Recent epidemiological trends estimate that the prevalence of RH is around 12–18% among patients with diagnosed hypertension [2]. The risk of having worse cardiovascular outcomes is twice higher in those patients when compared to essential hypertension [3]. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate alternative medication on their cardiovascular function.
Nitric oxide (NO) is the main endothelium-dependent vasodilator. NO disseminates to adjacent smooth muscle cells, leading to relaxation through guanosine triphosphate (GTP) conversion into cyclic guanosine monophosphate (cGMP) by guanylate cyclase enzyme [4]. The cGMP is degraded by phosphodiesterase 5 (PDE-5), widely expressed in whole body smooth muscles. Therefore, drugs that specifically inhibit PDE-5 increase the cGMP intracellular bioavailability and prolong its vasodilator effects [5]. In addition to the therapeutic effect on erectile dysfunction and pulmonary hypertension, several studies have shown that PDE-5 inhibitors improve BP and hemodynamics in essential hypertension [6,7].
Given the last decade's advances in the comprehension of RH pathophysiology and treatments, the authors intend to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of adults with RH. We believe that this systematic review can be relevant to guide clinician treatment choices and future research.
3.2. Blood pressure
3.3. Diastolic function
3.4. Endothelial dysfunction
3.5. Arterial wave reflection
3.6. Other hemodynamic variables
3.7. Plasma measurements
3.8. Side effects
4. Discussion
In this systematic review, we attempted to evaluate the effects of PDE-5 inhibitors on blood pressure and hemodynamics in this therapeutically challenging group of HR patients. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial dysfunction but they were not a consensus.
5. Limitations
Since five small, heterogeneous, and high-risk bias studies have been included in this systematic review, the evidence retrieved must be evaluated with caution. Four of them developed an acute protocol, but the experimental design was similar only in two articles. Furthermore, just one has developed a 14-day study of the effects of PDE-5 inhibitors in RH patients. For these reasons, it is difficult to draw firm conclusions regarding the impact of PDE-5 inhibitors on blood pressure and hemodynamics on RH. Nevertheless, RH consists of a very specific population with several challenges to enroll large numbers of participants, such as the high cardiovascular risk and a variety of associated comorbidities [1]. These peculiarities result in precluding safe withdrawal of medications and confounding interpretation of results, justifying studies with small sample sizes.
Another limitation is the possibility of publication bias. The failure to identify unpublished negative trials could lead to an overestimation of the effect of PDE-5 inhibitors on RH. However, to minimize publication bias, the search strategy included platforms that index ongoing clinical trials, congresses abstracts, academic papers (e.g., theses, dissertations, and monographs), among other publications. The authors also checked the references of all included articles and reviews retrieved by search terms.
6. Conclusion
Taking all data together, our systematic review suggests that PDE-5 inhibitors improve BP control, vascular hemodynamics, and diastolic dysfunction parameters. Our findings highlight the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Prolonged and larger studies are still needed to determine whether the beneficial cardiovascular effects of PDE-5 inhibitors on RH would be maintained with chronic administration. Future research should also focus on exploring the underlying molecular mechanisms that explain the hemodynamic benefits of PDE-5 inhibition in RH patients.
