A recent review reveals the significant risks heart failure patients face if they discontinue long-term drug treatments, which can include a rapid return to baseline and worsening rebound. The review focuses on patients with heart failure with reduced ejection fraction (HFrEF) and warns of persistent cardiovascular deterioration and a gradual decline from long-term benefits for those abruptly stopping foundational heart medications, even for short periods. “The totality of available evidence points to a meaningful clinical deterioration within a few weeks following the withdrawal for most drugs that have been evaluated for the treatment of heart failure,” said the authors of the paper, which appears in the Journal of the American College of Cardiology. “These findings suggest that that current emphasis on the implementation of foundational drugs needs to include an equally important emphasis to avoid even short-term gaps in treatment.” Supporting heart function Led by Khawaja M. Talha, MD, from the University of Mississippi Medical Center in Jackson, the review details the development of various heart failure drugs that have significantly improved patient outcomes by supporting heart function and reducing morbidity. These include angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, However, Dr. Talha’s team state that these treatments often require lifelong commitment, and many patients are unaware of the potential setbacks if they stop using these medications. These setbacks include a rapid return to baseline in which the stopping treatment of a certain drug can cause an immediate loss of the medication’s effects without adverse worsening of symptoms. However, such drugs are exceptions, with prazosin being a notable example. Another key finding identifies the worsening of rebound, where some medications, such as nitroprusside, can cause rapid clinical deterioration upon withdrawal. Muted changes The researchers suggest that this occurs as a counter-regulatory mechanism, previously suppressed by the drug, which become active and leads to heightened heart stress and worsening symptoms. “Rebound changes have been reported following the abrupt withdrawal of organic nitrates (i.e., isosorbide dinitrate) in patients with heart failure,” said the paper’s authors. “But the magnitude of such changes is substantially muted, and they do not affect all hemodynamic variables to a similar degree. “Counter-regulatory mechanisms to promote renal tubular sodium and water reabsorption are rapidly activated following the initiation of treatment with SGLT2 inhibitors, explaining the lack of a durable natriuretic or osmotic diuretic response during long-term treatment with these drugs.” Discontinuing treatment The review continues with discussions about the persistent cardiovascular deterioration observed in some patients in which some drugs have long-term detrimental effects that only become apparent after discontinuation. Here, medications such as milrinone and flosequinan can create dependency, where patients experience worse health outcomes after stopping them than before treatment began, which the review team attribute to underlying cardiotoxicity. The last key finding, which was observed with digoxin and SGLT2 inhibitors, involves drugs with sustained positive effects that when withdrawn, resulted in a slow but steady return to pre-treatment symptoms, suggesting these medications provided stable benefits. Digoxin withdrawal “Systemic reviews and meta-analyses have reported a similar pattern of benefit with digoxin while patients were receiving the drug and worsening of clinical status and an increase in hospitalizations for heart failure following its withdrawal,” they said. “The substitution of an alternative positive inotropic drug (milrinone) did not prevent the clinical deterioration seen following discontinuation of long-term digoxin therapy.” In concluding the review, the authors advise against unsupervised discontinuation of heart failure drugs, even during short hospital stays or other interruptions. Future directions Dr Talha and colleagues also reiterate a critical call to action that urges the exploration of newer therapies and their effects. “Worsening of clinical status with [current] drugs have been observed whether the effect of the drug was favorable or deleterious while patients were receiving them,” the authors wrote. “In many instances, the withdrawal of treatment was accompanied by rebound phenomena, when the discontinuation of therapy permitted unopposed counter-regulatory mechanisms to become manifest.” Sources: Talha KM, Butler J, Packer M. Consequences of Discontinuing Long-Term Drug Treatment in Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2024;84:2215-2232. Image Credit: ARMMY PICCA – stock.adobe.com