Hospital as opportunity
The patient’s 4-7 days in the hospital typically represent a “wonderful opportunity” to initiate all four drug classes in rapid succession and start uptitrations. But most hospitals and other health care settings, Dr. Vaduganathan observed, lack the structure and systems to support the process. Broad application will require “buy-in from multiple parties – from the clinician, from the patient, their caregivers, and their partners as well as the health system.”
Physician awareness and support for the strategy, suggests at least one of these experts, is probably much less of a challenge to its broad adoption than the bewildering mechanics of health care delivery and reimbursement.
“The problem is not education. The problem is the way that our health care system is structured,” said Milton Packer, MD, Baylor Heart and Vascular Institute, Dallas.
For example, sacubitril-valsartan and the SGLT2 inhibitors are still under patent and are far more expensive than longtime generic beta-blockers and MRAs. That means physicians typically spend valuable time pursuing prior authorizations for the brand-name drugs under pressure to eventually discharge the patient because of limits on hospital reimbursement.
Clinicians in the hospital are “almost disincentivized by the system” to implement management plans that call for early and rapid initiation of multiple drugs, Dr. Vaduganathan pointed out.
One change per day
There’s no one formula for carrying out the quadruple drug strategy, Dr. Vaduganathan noted. “I make only a single change per day” to the regimen, such as uptitration or addition of a single agent. That way, tolerability can be evaluated one drug at a time, “and then the following day, I can make the next therapeutic change.”
The order in which the drugs are started mostly does not matter, in contrast to a traditional approach that might have added new drugs in the sequence of their approval for HFrEF or adoption in guidelines. Under that scenario, each successive agent might be fully uptitrated before the next could be brought on board.
Historically, Dr. Packer observed, “you would start with an ACE inhibitor, add a beta-blocker, add an MRA, switch to sacubitril-valsartan, add an SGLT2 inhibitor – and it would take 8 months.” Any prescribed sequence is pointless given the short time frame that is ideal for initiating all the drugs, he said.
Hypothetically, however, there is some rationale for starting them in an order that leverages their unique actions and side effects. For example, Dr. Vaduganathan and others observed, it may be helpful to start an SGLT2 inhibitor and sacubitril-valsartan early in the process, because they can mitigate any hyperkalemia from the subsequent addition of an MRA.
That being said, “I don’t think we have firm evidence that any particular order is more efficacious than another,” Dr. Vaduganathan said. “It’s really about getting patients on all four drugs as quickly as possible, regardless of the sequence.”
Discussions about sequencing the drugs are “a distraction for our field,” Dr. Greene said. In trials, clinical benefit from the multiple-drug regimen has emerged almost right away once the drugs were on board. “The data clearly show that initiating all four, at least at low doses, gives the best bang for your buck and would be a high-yield strategy.”
Best evidence suggests that once all four agents have been started, attention can turn to uptitration, “with the beta-blocker as the higher priority,” Dr. Greene said. “The bottom line is to keep it simple: four drugs, simultaneously or within 1 week, and prioritize initiation at low doses to maximize tolerability.”
The four-drug approach yields survival and rehospitalization benefits even when uptitrations don’t reach prespecified goals, Dr. Fonarow observed. The SGLT2 inhibitors are started and maintained at the same dosage. But for the other three agents, uptitration should aim for the highest well-tolerated level, up to the target, even if the highest tolerated is the initial dosage.