The therapy of patients with Heart Failure with reduced ejection fraction (HFrEF) has evolved over the past several decades. Beta blockers; ACEIs, ARBs or sacubutril/valsartan; along with a MRA; a loop diuretic; and hydralazine/ISDN (in African Americans) form the basis of current guideline recommended therapy. Despite their use, even when appropriately dosed at target levels, there remains a considerable incidence of hospitalizations for Heart Failure (HHF) and cardiovascular mortality (CVM) as well as compromised quality of life and increased health care costs. The quest for effective therapies to further reduce cardiovascular outcomes in patients with HFrEF is therefore justified. Over the past several months 3 new therapies have been found to further reduce the combined primary endpoint of CVM and HHF in patients with HFrEF. The first class of agents the SGLT2is, in particular dapagliflozin and empagliflozin (DAPA-HF, EMPEROR-REDUCED), were effective in reducing CVM and HHF in patients with chronic HFrEF both in those with and without diabetes. The second agent, vericiguat, a nitric oxide stimulator, was evaluated in the VICTORIA trial in 2524 patients with HFrEF and reduced the combined primary endpoint of CVM and HHF with a HR of 0.90 (p=0.02). The third agent, omecamtiv mecarbil, a cardiac myosin activator that increases myocardial contractility without an increase in intracellular myocardial calcium concentration (but has been associated with an increase in troponin levels), was evaluated in the GALACTIC-HF Trial in 8256 patients with HFrEF. The GALACTIC-HF trial was recently announced to have reduced its primary endpoint of CVM and HHF with a HR of 0.92, p=0.0252. The details of the study results are however not as yet available and will be presented at the AHA in November 2020.

While the addition of three new classes that further reduce the combined endpoint of CVM and HHF is welcome it should be pointed out that, while dapagliflozin in DAPA-HF was shown to reduce both CVM and HHF, empagliflozin in EMPEROR–REDUCED significantly reduced only HHF, not CVM. However, a meta analysis of DAPA-HF and EMPEROR REDUCED, as well as the totality of evidence suggests that both of these SGLT2is are effective in reducing CVM as well as HHF. In contrast, neither vericiguat or omecamtiv mecarbil significantly reduced CVM. In regard to omecamtiv mecarbil it will be interesting to see whether or not its failure to reduce CVM was associated with its effect on cardiac troponin release, which potentially could indicate myocardial cell damage. Regardless, both agents reduce HHF and therefore should reduce healthcare costs. However, while we await further data on omecamtiv mecarbil as well as FDA and guideline committee review of these new agents, it might be of value to pause and consider how they will be sequenced into our clinical practice.

Should we add these three new agents to our current guideline recommended regimen for HFrEF, our patients will be taking a minimum of 6 drugs: a BB; ACE-I or ARB or sacubutril/valsartan; a MRA; a loop diuretic; a SGLT2i; vericiguat; and omecantiv mecarbil; and, in African Americans, hydralazine/ISDN.

In reality however our patients will be taking many more drugs since most will be on a statin and aspirin or another antiplatelet agent . Those with concomitant diabetes mellitus, approximately one third or patients with HFrEF, will likely be on metformin as well as possibly a GLP1 inhibitor, insulin, or other antidiabetic drugs. Those with concomitant atrial fibrillation will possibly be on an anti-arrhythmic agent in addition to anticoagulation. Many of our patients with HFrEF also have osteoarthritis and other chronic diseases associated with aging and obesity. In addition many will be taking over-the-counter vitamin supplements, fish oil, etc.

Compliance and tolerability to our guideline recommended Heart Failure medications was suboptimal prior to introduction of these 3 new classes and can be anticipated to be even worse after they are introduced into clinical practice.

In regard to sequencing of the available and likely soon to be available drugs my preference would be to prioritize those that have shown a reduction in CVM in addition to HHF. These include: BBs; ACEIs, ARBs or sacubutril/valsartan; a MRA; a SGLT2i: and, in African Americans, hydralazine/ISDN. While I would consider adding vericiguat and or omecamtiv mecarbil in those with recurrent HHF and or worsening signs or symptoms I would suggest that they be added only after assuring that the patient is stable on the agents shown to reduce CVM at their target dose. Further studies will be required to determine the characteristics of the subset of patients that might benefit most from vericiguat and omecamtiv mecarbil. While both drugs significantly reduce HHFs their reduction is rather modest, 10% for vericiguat and 8% for Omecamtiv Mecarbil. In view of their marginal benefit their cost effectiveness should play an important role in the decision as to in who and when they should be used.

Regardless of the benefit of these three new classes of drugs their benefit in the “real world“ will depend on patient compliance and tolerability, which as pointed out above, was suboptimal even before their introduction. Our colleagues in hypertension have found that compliance of currently available antihypertensive agents is relatively poor and that optimal blood pressure control is best achieved with single pill combination therapy such as a thiazide diuretic and an ACE-I or an ACE-I and a calcium channel blocking agent, such as amlodipine. These single pill combination preparations are now first line therapy for patients with hypertension. In Heart Failure, in contrast, we have been reluctant to advocate and evaluate the use of combination therapy. It has been thought that combination therapy would limit dose adjustments and individualization of therapy. However, many of the drugs that we currently or likely will soon to be used in patients with HFrEF have a narrow dose range or, in the case for example of the SGLT2i empagliflozin, a single daily dose of 10 mg. It should therefore be possible to develop single pill combination products that can be given once a day with 1-3 dose regimens. The single pill combinations should demonstrate not just convenience but an additive or synergistic effect. For example, the combination of a MRA + a loop diuretic would: 1) provide added sodium loss and plasma volume reduction 2) provide added potassium loss and thus diminish the risk of hyperkalemia. A number of other combinations can be contemplated such as sacubutril/valsartan and a MRA; a SGLT2i + a MRA, or possibly a triple combination of all 3 drugs. One can imagine several other combinations. It will however take some time to develop these combinations, gain regulatory approval and demonstrate their efficacy and safety. The longer we wait to initiate this process the more new drugs are likely to be added to our patients with HFrEF with a likely further decrease in patient compliance and tolerability. While we should continue our quest to find new drugs and approaches to further reduce CVM and HHF in patients with HFrEF these efforts are unlikely to further reduce cardiovascular outcomes if we do not begin to find ways to increase patient compliance and tolerability.

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