Drug Therapy for Acute and Chronic Heart Failure with Preserved Ejection Fraction with Hypertension: A State-of-the-Art Review

Diuretics play a crucial role in the management of HFpEF, particularly in addressing the hallmark features of abnormal fluid distribution and fluid overload [44]. In the acute phase of HF, most patients present to the emergency department with symptoms of volume overload [45]. Loop diuretics, such as furosemide, are the primary treatment approach for reducing congestive symptoms associated with hypervolemia in patients with HFpEF [46]. Diuretics enhance sodium and water excretion in urine, effectively decreasing blood volume and blood pressure. Consequently, intravenous diuretics are commonly used in the treatment of patients with HFpEF in the acute phase with concurrent hypertension.

Patients with HFpEF have a narrow range of sensitivity to volume changes, with a fine line between hypervolemia, leading to congestive symptoms, and hypovolemia. The diuretic response can be evaluated by measuring the urinary potassium to creatinine ratio in patients with acute HFpEF [47]. Overly aggressive diuresis can potentially reduce the cardiac output, decrease renal function, and cause hypotension [48, 49]. In light of this, the ROPA-DOP trial investigated whether the combination of dopamine and furosemide could minimize worsening renal function in patients with HFpEF [50]. Furosemide was associated with renal impairment, and dopamine did not significantly affect creatinine levels, highlighting the persistent challenge of renal impairment associated with diuretic therapy. Another concern is the development of diuretic resistance with chronic loop diuretic use [51, 52], characterized by an inadequate reduction in edema despite the use of a maximal diuretic dose [53]. Moreover, clinicians should exercise caution when initiating loop diuretics or escalating the dose of loop diuretic in patients treated with other agents, such as sacubitril/valsartan [54] and empagliflozin [55] in patients with HFpEF, owing to the increased risk of volume depletion.

The use of intravenous diuretics in the acute phase of HFpEF can effectively alleviate symptoms of congestion associated with fluid overload, which may in turn lead to a reduction in blood pressure. However, chronic diuretic therapy may contribute to renal impairment, and overly aggressive diuresis can lead to hypotension. Therefore, the optimal balance between achieving an ideal fluid status and avoiding adverse effects necessitates careful consideration when administering diuretics in the treatment of HFpEF with concurrent hypertension. In patients with CKD, the administration of loop diuretic agents should be maintained at the lowest effective dose. Preferred alternatives include evidence-based agents with diuretic effects, such as mineralocorticoid receptor antagonists (MRAs) with careful serum potassium level monitoring, and sodium–glucose co-transporter 2 (SGLT2) inhibitors [56]. Thiazide diuretics may also be considered in combination with loop diuretics to enhance the effectiveness of diuretics [57].

In the TOPCAT trial that studied the usefulness of spironolactone, an MRA, in 3445 patients with HFpEF [58], a significant proportion of patients were receiving diuretic medications at baseline. Specifically, among the 1767 patients enrolled in the Americas, approximately 89% were receiving a diuretic at baseline, whereas in Georgia/Russia, approximately 74% were receiving a diuretic at baseline [58, 59]. A sub-analysis of the TOPCAT trial indicated that baseline diuretic use was associated with a higher risk of all-cause hospitalization, but not with all-cause mortality in patients with HFpEF. However, the sub-analysis did not report whether diuretic use led to changes in blood pressure [59].

Aldosterone receptor blockade can be beneficial in patients with HF, as MRAs are believed to prevent many of the maladaptive effects of aldosterone on the cardiovascular system. For example, spironolactone is hypothesized to prevent the aldosterone-mediated collagen synthesis that contributes to LV remodeling [60].

In the Aldo-DHF trial, in patients with HFpEF, long-term therapy with spironolactone improved LV diastolic function but did not affect maximal exercise capacity, HF symptoms, or quality of life [61]. In the TOPCAT trial, spironolactone did not significantly reduce cardiovascular mortality, but it did significantly reduce HF hospitalization. Moreover, spironolactone significantly reduced systolic blood pressure (SBP) [62]. This was only apparent in the patient cohort from the Americas, who had a baseline SBP of 129 (118–138) mmHg, while those in Georgia/Russia had a baseline SBP of 130 (120–140) mmHg. With spironolactone, the average magnitude of SBP reduction was 4.2 mmHg and 0.6 mmHg in the patients from the Americas and Russia/Georgia, respectively [58]. These findings suggest that there may be regional variations in the blood pressure response to spironolactone. However, maximal exercise capacity, HF symptoms, and quality of life appear to be unaffected by spironolactone. Although there was a trend toward a reduction in cardiovascular mortality, the observations were not statistically significant; however, a reduction in HF hospitalization was observed with spironolactone in the TOPCAT trial, which is why MRAs have a class IIb recommendation in HFpEF [17].

Another study based on the results of the TOPCAT trial [63] evaluated the heterogeneous treatment effects of spironolactone in patients with HFpEF. The study revealed that spironolactone reduced the risk of cardiovascular death in those with a high body mass index (defined as > 31.71 kg/m²) and a high white blood cell count (> 6.6 cells/µL), but it increased the risk of cardiovascular death in those with a low body mass index (defined as ≤ 31.71 kg/m²) and low alkaline phosphatase (≤ 80 U/L), indicating that the response to spironolactone may vary among different patient populations.

A recent study used a machine-learning approach to identify responders and non-responders to spironolactone among patients with HFpEF. The derivation cohort was obtained from the Aldo-DHF trial, and the validation cohort was obtained from the TOPCAT trial. The machine-learning approach identified that early mitral filling velocity/early diastolic mitral annular velocity ratio (E/e’) significantly improved in spironolactone responders in the derivation cohort, and spironolactone significantly reduced the occurrence of the primary outcome (composite of cardiovascular mortality, aborted cardiac arrest, and HF hospitalization) among responders, but not among non-responders [64].

A secondary analysis of the TOPCAT trial also evaluated the benefits of spironolactone as an add-on therapy for patients with HFpEF with resistant hypertension (defined as an SBP ≥ 130 mmHg and/or a diastolic blood pressure ≥ 80 mmHg despite the use of an angiotensin-converting enzyme inhibitor [ACEI]/angiotensin receptor blocker [ARB], calcium channel blocker, and diuretic, or using ≥ 4 classes of anti-hypertensive medication). The risk of the composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization was significantly lower in the group receiving spironolactone, whereas the risk of the composite outcome was not significantly different for patients without resistant hypertension. A significant interaction was observed between spironolactone and resistant hypertension in HFpEF. Therefore, the study suggested that spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension [65].

Vasodilators play a vital role in the management of HFpEF by addressing the relaxation impairment (diastolic dysfunction) that is characteristic of the condition. In HFpEF, the ability to tolerate rapid increases in afterload is reduced, which can lead to pulmonary edema. Direct vasodilators, such as nitroglycerin, hydralazine, and nesiritide, are used to dilate the blood vessels, which in turn reduces the blood pressure and afterload. This improves the cardiac output and diminishes the risk of pulmonary edema.

Although nitrates are commonly prescribed to enhance exercise capacity in patients with HFpEF, their clinical evidence is limited. Exercise limitation is a significant chronic symptom in HFpEF [66], prompting treatment with nitrates in approximately 15–50% of the patients [51, 67]. However, the risk of excessive hypotension must be considered. Practice guidelines from the American College of Cardiology (ACC)/American Heart Association (AHA) [17] and the Heart Failure Society of America (HFSA) [68] acknowledge a potential role for nitrates in alleviating HFpEF symptoms but highlight the risk of nitrate-induced hypotension in older patients with HFpEF. In the ACC/AHA 2022 guidelines, avoidance of routine use of nitrates is stated, with a class III recommendation [17]. Moreover, older patients with HFpEF often exhibit autonomic dysfunction, chronotropic incompetence, and altered baroreflex sensitivity. These factors can exacerbate the hypotensive responses to changes in hemodynamic load, subsequently increasing nitrate intolerance [69].

Studies evaluating the efficacy of vasodilators in HFpEF have yielded contradictory results. The NICHE trial suggested that the combination of hydralazine and isosorbide dinitrate may improve exercise capacity in HF (6-min walk test); however, this effect diminished after adjusting for baseline covariates. Nevertheless, the rates of HF hospitalization and mortality were lower with the combination of hydralazine and isosorbide dinitrate than with standard of care [70]. The study did not identify significant differences in cardiac structure and function, although the possibility of being underpowered was acknowledged. However, the NEAT-HFpEF trial, which evaluated the use of isosorbide mononitrate in patients with HFpEF, showed no significant difference in peak oxygen consumption between the isosorbide mononitrate and placebo groups. Compared with placebo, isosorbide mononitrate failed to demonstrate a significant improvement in exercise capacity [71]. Another study investigating isosorbide dinitrate, with or without hydralazine, failed to demonstrate beneficial effects on LV remodeling or submaximal exercise capacity, and suggested that it was poorly tolerated in patients with HFpEF. Consequently, routine use of vasodilators in HFpEF was not supported in that study [72]. The ROSE study evaluated whether the addition of low-dose nesiritide to diuretic therapy would enhance decongestion and preserve renal dysfunction in patients with HF regardless of ejection fraction; the addition of nesiritide had no effect on decongestion, renal function, or clinical outcomes [73]. Another study compared hemodynamic responses to nitroprusside in patients with HFpEF with those of patients with HF with reduced ejection fraction. The study demonstrated that the decrease in systemic arterial pressure with nitroprusside was greater in patients with HFpEF than in those with HF with reduced ejection fraction. The study concluded that patients with HFpEF experienced greater blood pressure reduction with nitroprusside [74].

Given the conflicting results on the benefits of vasodilators, further clarification is needed to determine whether the combination of isosorbide dinitrate and hydralazine enhances exercise capacity in patients with HFpEF, and to clarify the benefits that can be achieved with vasodilators generally in patients with HFpEF.

Inotropes, including dobutamine and milrinone, play a role in managing severe HFpEF by enhancing cardiac contractility and increasing cardiac output. These parameters can be measured by echocardiography and bioreactance methods, although the methods cannot be used interchangeably as they provide different cardiac output values at rest and during dobutamine stress tests. Bioreactance is advantageous because it can be used to continuously monitor key hemodynamic variables, including cardiac output, stroke volume, and heart rate, and it demonstrates good test–retest reliability for estimating cardiac output and stroke volume at rest and after stress testing, such as with dobutamine, to evaluate cardiac function [75].

The MilHFpEF study investigated extended-release milrinone, a phosphodiesterase type III inhibitor, and found it to be well-tolerated by patients, with an improvement in their quality of life [76]. Regarding blood pressure control, another study investigated milrinone and observed a reduction in the mean pulmonary artery pressure from 23 ± 2 to 19 ± 4 mmHg; however, the mean arterial pressure remained unchanged. The study also demonstrated a decrease in LV filling pressure without any changes in the stroke volume, indicating an improvement in LV compliance [77]. These findings suggest that inotropic agents, such as milrinone, may effectively enhance cardiac function and contribute to symptom improvement in patients with HFpEF.

However, it is important to note that the 2022 ACC/AHA guidelines only recommend inotropes with a class IIa/IIb recommendation in patients with advanced HF who are awaiting mechanical circulatory support or heart transplantation, which is mostly (but not exclusively) patients with HF with reduced ejection fraction [17]. Moreover, the ROSE study tested the hypothesis that the addition of low-dose dopamine (inotrope) to diuretic therapy enhances decongestion and preserves renal function in patients with acute HF, regardless of ejection fraction. The addition of low-dose dopamine did not enhance decongestion or improve renal function when added to diuretic therapy, so this strategy was not supported [73].

Given the conflicting findings and the shortage of evidence on blood pressure control in patients with HFpEF with hypertension specifically, further research is needed to establish the benefits of inotropes and to better understand their impact on blood pressure control in the context of HFpEF with hypertension.

In the management of acute HFpEF, intravenous medications are commonly administered to address the challenges associated with afterload reduction and preload adjustment. In such cases, calcium channel blockers and nitrates are frequently used. Nitrates adjust the preload by expanding the venous pool and reducing the amount of blood returning to the heart. Calcium channel blockers exert their effects by dilating the blood vessels, leading to a decrease in the afterload and improved cardiac function. Intravenous beta-blockers are often administered in acute settings with the primary aim of lowering the heart rate and improving cardiac function. By blocking the action of catecholamines on beta-adrenergic receptors, beta-blockers slow heart rate, thereby improving filling and cardiac output. However, they may still have an impact on blood pressure, which varies depending on the hemodynamic status of the patient. In the chronic HF phase, oral beta-blockers are more commonly prescribed for long-term heart rate control and their additional benefits in managing blood pressure. The use of oral beta-blockers is described in more detail in the following sections.

A retrospective analysis comparing intravenous labetalol (beta-blocker) and intravenous nicardipine (calcium channel blocker) in the intensive care setting for patients with acute elevations in systolic or diastolic blood pressure suggested that nicardipine exhibits greater efficacy as an anti-hypertensive agent than labetalol. The use of nicardipine was associated with fewer adverse effects, such as bradycardia, hypotension, or atrioventricular block, and had lower discontinuation rates than labetalol [78]. These findings were supported by the multicenter randomized CLUE trial, which compared the safety and efficacy of Food and Drug Administration-recommended dosing of intravenous nicardipine with intravenous labetalol for the management of acute hypertension. Patients treated with nicardipine were more likely to achieve the target SBP range within 30 min than those treated with labetalol [79]. Note that these studies were conducted in a general hospitalized patient population with acute hypertension. Although patients with concomitant HF were included, the findings were not specific to the population of patients with HFpEF. Therefore, the applicability of these results to the management of hypertension in patients specifically diagnosed with HFpEF requires further investigation and clinical consideration.

ACEIs and ARBs contribute to HF management by targeting the renin–angiotensin–aldosterone system, effectively reducing blood pressure, enhancing cardiac function through afterload reduction, and relieving the heart's workload. Although their benefits in patients with HF with reduced ejection fraction have been well established, showing reductions in morbidity and mortality [80, 81], in patients with HFpEF, the outcomes have been less promising across large-scale clinical trials. The CHARM-PRESERVED study demonstrated a moderate and borderline significant trend toward an 11% reduction in combined cardiovascular mortality or HF hospitalization with candesartan compared with the placebo [82]. The PEP-CHF trial, which evaluated perindopril, showed improvements in symptoms and exercise capacity but not in the combined all-cause mortality or cardiovascular hospitalization compared with the placebo [83]. Finally, the I-PRESERVE trial evaluating irbesartan did not demonstrate a significant reduction in cardiovascular hospitalization or all-cause mortality compared with placebo in patients with HFpEF [67]. Nonetheless, all three trials reported a significant decrease in blood pressure over time with the active drug compared with the placebo, highlighting the effectiveness of ACEIs/ARBs in blood pressure control [67, 82, 83].

Angiotensin receptor–neprilysin inhibitor (ARNI) is a combination therapy comprising an ARB and a neprilysin inhibitor [84]. Currently, sacubitril/valsartan (LCZ696) is the only available ARNI. ARNI blocks the angiotensin II receptor and inhibits the breakdown of natriuretic peptides, leading to vasodilation, reduced sodium retention, and improved cardiac function.

In the phase II PARAMOUNT trial, sacubitril/valsartan demonstrated favorable effects in patients with HFpEF. It reduced the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, left atrial enlargement, and improved New York Heart Association (NYHA) functional class compared with valsartan alone. Moreover, sacubitril/valsartan demonstrated a significant reduction in systolic and diastolic blood pressure after 36 weeks of treatment compared with valsartan alone [85]. These findings were further supported by another study, which showed that sacubitril/valsartan reduced NT-proBNP concentration and heart rate, improved the signs and symptoms of HF, and led to improvements in NYHA functional class and E/e’ [86]. The PIONEER-HF trial investigated the use of sacubitril/valsartan in patients with acute decompensated HF. It demonstrated that early initiation of sacubitril/valsartan following stabilization resulted in a significantly lower risk of cardiovascular death or HF rehospitalization compared with enalapril at 8 weeks [87].

The PARAGON-HF trial evaluated the efficacy of sacubitril/valsartan compared with valsartan alone in patients with HFpEF. Although the reduction in events with sacubitril/valsartan was not statistically significant, there was a 13% risk reduction, primarily driven by a 15% reduction in hospitalizations [88]. These positive outcomes led to the approval of sacubitril/valsartan as the first drug therapy indicated for the treatment of HFpEF in 2021.

In terms of blood pressure control, in the PARAGON-HF trial, patients in the sacubitril/valsartan group had a higher incidence of hypotension than those in the valsartan group. However, they were less likely to experience increases in creatinine and potassium levels, which are indicators of kidney function. At 8 months, the mean SBP was 4.5 mmHg lower in the sacubitril/valsartan group (approximately 130 mmHg) compared with the valsartan group (approximately 135 mmHg). However, this difference was not correlated with the potential treatment effect [88]. A recent post hoc analysis of the PARAGON-HF trial evaluated the effect of neprilysin inhibition on resistant hypertension (defined as an SBP ≥ 140 mmHg despite treatment with valsartan, a calcium channel blocker, and a diuretic) in patients with HFpEF. The reduction in SBP at weeks 4 and 16 was greater with sacubitril/valsartan than with valsartan alone in patients with resistant hypertension, and the proportion of patients with resistant hypertension who achieved SBP control by week 16 was 47.9% with sacubitril/valsartan and 34.3% with valsartan alone [89]. These findings suggest that the combination of sacubitril with valsartan may be particularly beneficial in patients with HFpEF with resistant hypertension.

Another study of data from 4796 patients with HFpEF from the PARAGON-HF trial first evaluated the influence of pulse pressure (an indicator of hypertension and arterial stiffness) on the PARAGON-HF primary endpoint of total HF hospitalizations and cardiovascular death, showing that patients in the highest pulse pressure quartile had a higher rate of the primary endpoint, total HF hospitalizations, and myocardial infarction than patients in the second pulse pressure quartile. Then, reductions in pulse pressure with sacubitril/valsartan treatment were associated with a decreased risk of the primary endpoint and total HF hospitalizations. One year after randomization, pulse pressure was significantly lower in the sacubitril/valsartan group than in the valsartan group. These findings suggest that pulse pressure is an independent predictor of cardiovascular events in patients with HFpEF, and that sacubitril/valsartan reduces pulse pressure to a greater degree than valsartan alone [90].

In the ARNIMEMs-HFpEF trial, sacubitril/valsartan improved functional capacity, lung congestion, and quality of life [91]. In addition, the trial demonstrated a significant reduction in mean pulmonary arterial pressure with sacubitril/valsartan, independent of loop diuretic management. The transition to sacubitril/valsartan resulted in a reduction in the mean pulmonary arterial pressure, by 4.99 mmHg, accompanied by significant improvements in 6-min walking distance and quality of life. Moreover, between the ARNI On and ARNI Off periods, the mean pulmonary arterial pressure rebounded by + 2.84 mmHg [91]. In addition, a study by Burgdorf et al. reported a significant reduction in pulmonary arterial pressure after transitioning to sacubitril/valsartan in patients with HFpEF and pulmonary hypertension [92].

A phase IV, multicenter, prospective, randomized, open-label study assessing the effect of in-hospital initiation of sacubitril/valsartan on NT-proBNP in patients admitted with an acute exacerbation of HF (PREMIER) is currently enrolling patients in Japan [93]. The PREMIER study is anticipated to reach primary completion in May 2024.

Beta-blockers, such as carvedilol and metoprolol, are frequently used in the management of HFpEF to effectively reduce heart rate and alleviate the workload on the heart. By reducing the sympathetic stimulation effects, oral beta-blockers can lower heart rate and decrease peripheral vascular resistance, thereby helping in the regulation of blood pressure. This dual mechanism renders them valuable in optimizing both heart rate and blood pressure control in patients with stable HF. Notably, a higher heart rate is associated with poor outcomes in patients with HFpEF who have sinus rhythm [94, 95].

In the SWEDIC trial, treatment with carvedilol demonstrated significant improvement in early filling/atrial filling ratio in patients with HF due to LV relaxation abnormalities; this effect was particularly pronounced in patients with higher heart rates at baseline. However, the study also acknowledged the limitations of Doppler echocardiographic indices in assessing LV diastolic dysfunction in this population [96]. The OPTIMIZE-HF registry did not identify a relevant prognostic effect of beta-blockers in older patients with HFpEF [5], potentially owing to underdosing [97] or the relatively short follow-up duration (median, 2.2 years) [98]. Additionally, the benefits of beta-blockers appeared to manifest after three years but not at the 1-year follow-up in patients with HFpEF in another study [99]. Six-year follow-up data from the OPTIMIZE-HF registry showed that high-dose beta-blocker therapy in patients with HFpEF and elevated heart rate (≥ 70 beats/min) was associated with a significantly lower risk of death, where the all-cause mortality rates were 63% and 68% in the matched patients receiving high-dose beta-blocker and no beta-blocker, respectively [100]. Similarly, in another study, the use of beta-blockers was associated with lower all-cause mortality but not with combined all-cause mortality or HF hospitalization [101]. A meta-analysis of randomized controlled trials showed a potential mortality reduction with beta-blockers in HFpEF, although statistical significance was not reached [102]. In the ELANDD study, nebivolol treatment for 6 months reduced the heart rate but did not enhance the exercise capacity or peak oxygen consumption in patients with HFpEF [103]. The J-DHF study, which enrolled Japanese patients with HFpEF, suggested that standard-dose carvedilol (> 7.5 mg/day) may be effective in reducing the composite outcome of cardiovascular death and unplanned HF hospitalization; however, the study was underpowered, and the findings were not conclusive [104].

Although beta-blockers demonstrate some promise in the management of HFpEF, the findings remain inconclusive and may be influenced by factors such as dosage and follow-up duration. Moreover, some clinicians suspect that beta-blockers may worsen HFpEF, particularly in patients with chronotropic incompetence, which is why this drug class does not currently carry any recommendation in existing guidelines and they are not the first choice for the treatment of hypertension in patients with HFpEF [17].

As stated in the AHA/ACC/HFSA guidelines, non-dihydropyridine calcium channel blockers, such as diltiazem and verapamil, have negative inotropic effects and are generally not well tolerated in HF owing to their myocardial depressant activity. However, second-generation dihydropyridine calcium channel blockers, such as amlodipine and felodipine, exhibit less myocardial depressant activity and can help in reducing peripheral vasoconstriction and LV afterload [17]. Non-dihydropyridine calcium channel blockers have a class III recommendation in stage B HF with an ejection fraction < 50%, and all calcium channel blockers are contraindicated in patients with HF with reduced ejection fraction [17]; however, there is no indication that they cause harm in patients with HFpEF; therefore, they may be used to control hypertension in this population.

Calcium channel blockers, including amlodipine and diltiazem, are commonly prescribed for hypertension, but their use in patients with chronic HFpEF and hypertension should be given lower priority compared with other medications, such as ACEIs/ARBs, ARNI, and MRAs. Findings from OPTIMIZE-HF showed that the primary composite endpoint of all-cause mortality and HF hospitalization occurred in 82% and 81% of patients with HFpEF who received and did not receive calcium channel blockers, respectively. Similar results were observed when patients were categorized according to the administration of amlodipine and non-amlodipine calcium channel blockers. These results suggest that the prescription of calcium channel blockers, regardless of the class, does not have an association with the composite endpoint or individual endpoints of all-cause mortality, HF hospitalization, and all-cause hospitalization in patients with HFpEF [105]. Primary HF prevention mainly depends on decreasing blood pressure [106]. While calcium channel blockers are effective for controlling blood pressure in patients with hypertension, multiple studies have demonstrated that they may be less protective against HF development than other anti-hypertensive agents [107, 108]. For instance, the CONVINCE trial reported a 30% higher incidence of HF in patients treated with verapamil than in those treated with diuretics [109]. Furthermore, a meta-analysis of 18 randomized clinical trials revealed a 25% increase in HF risk among patients with hypertension using intermediate-acting dihydropyridine calcium channel blockers [110]. The significance of this evidence in guiding the selection of calcium channel blockers as anti-hypertensive agents and their impact on primary HF prevention warrants further research.