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How much drug-induced blood pressure reduction is effective and safe in heart failure?

Sciarretta, Sebastianoa,c; Volpe, Massimob,c

doi: 10.1097/HJH.0000000000002142
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aDepartment of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, Latina

bDepartment of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome

cIRCCS Neuromed, Località Camerelle, Pozzilli, Italy

Correspondence to Massimo Volpe, MD, Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Via di Grottarossa 1035, Rome, Italy. E-mail: massimo.volpe@uniroma1.it

High blood pressure (BP) is a major risk factor for the development of cardiovascular events and mortality, and the risk of cardiovascular disease is directly correlated with BP levels also within the range of normality [1]. In the last decades, intervention studies and clinical trials clearly demonstrated that a pharmacological reduction of BP reduces cardiovascular mortality and morbidity in patients with hypertension and/or high cardiovascular risk [1]. Recently, the SPRINT trial also demonstrated that an intensive antihypertensive treatment reducing SBP to 120 mmHg or less was significantly more effective in the reduction of cardiovascular events than standard treatment in nondiabetic individuals with high baseline cardiovascular risk [2]. Based also on additional evidence, 2018 European guidelines for the treatment of hypertension suggest to lower SBP to 130 mmHg in patients with age more than 65 years and to even lower levels (120–129 mmHg) in younger patients (<65 years) [3].

On the other hand, an exaggerated reduction of BP may be associated with adverse events leading to drug discontinuation. In addition, post hoc analyses of INVEST, ONTARGET and TNT trials previously showed that excessive reductions of BP in different clinical settings of a high cardiovascular risk were associated with increased cardiovascular events or mortality at univariate analysis, although similar effects were not observed in other trials [4,5]. Caution in BP reduction should also be exerted in patients with cerebrovascular diseases, diabetes and renal insufficiency as in these patients, exaggerated BP decreases may have detrimental effects. Therefore, optimal BP targets may vary across different individuals, very likely as a consequence of other associated conditions and comorbidities. For these reasons, efficacy and tolerability of BP-lowering therapy should be elucidated in patients with different clinical features.

In this perspective, the BP levels to be achieved with treatment is of particular importance in patients with heart failure [6]. Although antihypertensive drug classes, such as renin–angiotensin–aldosterone system (RAAS) inhibitors and beta-blockers are routinely administered to this category of individuals in whom they reduce hospitalization, delay progression of disease and increase survival, it is not known whether the beneficial effects of these drugs are dependent on the extent of the BP reduction [7]. It should also be mentioned that the management of BP in patients with heart failure is complex. Previous results obtained in these individuals showed a J-shaped relationship between BP levels and cardiovascular events, although it remains unclear whether a low BP is the cause or the consequence of a more severe clinical status [8].

In order to address these unsolved issues, Pinho-Gomes et al.[9] conducted a systematic review and meta-analysis aimed at evaluating: the extent of a BP reduction induced by the antihypertensive drugs usually administered to patients with heart failure; the correlation between the extent of BP reduction induced by antihypertensive agents and the incidence of cardiovascular or adverse events leading to drug discontinuation; the impact of baseline SBP levels on efficacy and safety of BP-lowering therapy in heart failure. The analysis included 37 randomized clinical trials published from 1986 to 2017, which enrolled a total number of 91 950 patients with chronic symptomatic heart failure. Inclusion criteria for these trials were randomization of patients to either placebo or BP-lowering drugs; or randomization of patients to two different BP-lowering agents. Among the considered trials, 30 included patients with heart failure with reduced ejection fraction, four included patients with heart failure with preserved ejection fraction and three included both the above conditions, resulting in a rather heterogeneous population.

An important result of the study was that BP-lowering agents significantly reduced SBP by 2.4 mmHg with respect to placebo, with RAAS inhibitors being the most effective drugs (3.2 mmHg reduction). On the other hand, no significant differences in SBP reduction were observed when different BP-lowering drugs were directly compared. In addition, when the extent of SBP reduction was correlated with cardiovascular outcomes, which included hospitalization for heart failure, cardiovascular death and total mortality, no significant association was detected. Finally, the analysis confirmed that BP-lowering agents significantly reduce hospitalization and cardiovascular death with respect to placebo. This result suggests that an intensive BP reduction strategy aimed at the reduction of SBP below the optimal levels may not be significantly effective in patients with chronic heart failure, although a recent analysis from the SPRINT trial showed that an intensive BP reduction strategy significantly prevents heart failure occurrence in nondiabetic patients with high cardiovascular risk [10]. The results also suggest that the beneficial effects induced by antihypertensive agents in patients with heart failure may not primarily depend on BP reduction but more on neurohormonal and antiremodeling effects of the antihypertensive drugs.

Another intriguing result of this meta-analysis was that the extent of SBP reduction induced by antihypertensive drugs was also not significantly correlated with the incidence of adverse events leading to drug discontinuation. These data suggest that a treatment of heart failure patients with BP-lowering agents is relatively safe and SBP reduction is well tolerated. The use of antihypertensive agents appears to be encouraged, without significant concern, also in patients with lower baseline SBP levels. In fact, the analysis by Pinho-Gomes et al. showed that baseline SBP levels do not affect the incidence of cardiovascular outcomes or adverse events in patients treated with BP-lowering agents. Therefore, although cardiologists are sometimes concerned to prescribe a BP-lowering therapy to patients with heart failure and low SBP levels (<120 mmHg), these results may suggest that this treatment may be equally effective and safe in these individuals [8].

Several additional considerations are generated by this meta-analysis. First, because of the low number of studies, it was not possible to perform subgroup analyses. In this context, it would have been interesting to correlate the extent of SBP reduction with cardiovascular outcomes in patients with and without hypertension. In fact, previous evidence indicated that a significant BP reduction should be pursued in hypertensive patients with heart failure and current heart failure guidelines suggest to reduce SBP levels to 130 mmHg in these individuals [8,11]. Therefore, it is very likely that the observed lack of association between SBP reduction and cardiovascular outcomes may be true for patients with baseline normal BP levels but not for those with altered levels. It would have been interesting to check both efficacy and safety of SBP reduction also in other subgroups of patients, such as those with diabetes, renal insufficiency, different NYHA classes and reduced or preserved ejection fraction. It is likely that the correlation between SBP reduction and cardiovascular outcomes or adverse events may vary across these different categories of individuals. So, there is room for further studies and analyses.

Cardiovascular outcomes considered in the current meta-analysis did not include myocardial infarction, stroke and renal insufficiency. Therefore, it will be important to check in the future the impact of SBP reduction on these outcomes in patients with heart failure.

In addition, in the meta-analysis by Pinho-Gomes et al.[9], SBP levels at the end of titration period were considered for calculating SBP reduction with respect to baseline. Future studies should consider SBP values at the end of the study to calculate SBP reduction, as they may reflect more accurately the effects of antihypertensive therapy over time.

Finally, some additional considerations regarding the safety of SBP reduction by drugs in heart failure should be done. In the meta-analysis by Pinho-Gomes et al.[9], SBP reduction did not significantly correlate with the incidence of adverse events leading to discontinuation of the therapy. However, it should be pointed out that patients enrolled in the trials included in the meta-analysis were initially followed up after starting the therapy for an optimal titration of the dose of the drug. A similar approach may be recommended in the clinical practice. Remarkably, the current meta-analysis did not rule out the possible existence of a J-shaped effect of antihypertensive therapy and future studies are mandatory to address this issue.

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ACKNOWLEDGEMENTS

Funding: This work was partially supported by the grant ‘Ricerca corrente’ of the Italian Ministry of Health to M.V.

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Conflicts of interest

There are no conflicts of interest.

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