Dreaming of a cardiovascular drug sanctuary: Why some old drugs still matter

As cardiovascular physicians, we live in exciting times. New treatment options become available, new mechanisms are targeted and therapeutic strategies grow increasingly precise. Inevitably, some older medications fall out of favour in routine clinical practice while sometimes retaining relevance as research tools. Yet, some prototypical drugs or entire drug classes vanish completely, becoming unavailable for, both, patient care and clinical investigation. Against the background of rapid innovation, renewed interest in older drugs like colchicine in cardiovascular medicine appears paradoxical. Are we romanticizing the past or is there a need for a cardiovascular drug sanctuary? Colchicine's unique anti-inflammatory actions target mechanisms implicated in the pathogenesis of left ventricular hypertrophy.1, 2 The COLCAD trial was a randomized, double-blind, placebo-controlled study designed to test whether low-dose colchicine could reduce left ventricular hypertrophy in patients with coronary artery disease.3 Sixty-six adults with established coronary artery disease, echocardiographically defined left ventricular hypertrophy and well-controlled blood pressure were assigned to colchicine 0.6 mg daily or to placebo for 48 weeks. The primary outcome was the change in left ventricular mass indexed to body surface area, measured by cardiac magnetic resonance imaging. After 48 weeks, there was no significant difference in left ventricular mass regression between the colchicine and placebo groups. Similarly, no relevant treatment effects were observed for left ventricular or left atrial volumes, inflammatory markers, glycaemic parameters or body mass index. Recruitment was stopped prematurely because of slow enrolment, resulting in a sample size substantially smaller than originally planned. Consequently, the study was underpowered to detect modest but potentially meaningful effects. In any event, colchicine did not demonstrate a measurable benefit on left ventricular hypertrophy, even though benefits have been reported in other cardiovascular indications.4, 5 The neutral findings underscore the limited impact of anti-inflammatory therapy on left ventricular hypertrophy in patients with low residual inflammatory activity and optimized cardiovascular treatment. Most participants had low baseline levels of systemic inflammation, good blood pressure control and were on renin-angiotensin system inhibitors, all of which reduce the likelihood of further structural regression. In addition, cardiac magnetic resonance imaging revealed relatively modest ventricular hypertrophy in many patients, raising concerns about target misclassification. Rather than excluding a role for colchicine, the study emphasizes the need for more precise patient selection. Future trials should preferentially include patients with clearly defined hypertrophy on magnetic resonance imaging, higher inflammatory burden or ongoing hemodynamic stress, where anti-inflammatory interventions may be more likely to show benefit. Beyond colchicine, long-established cardiovascular drugs are undergoing renewed investigation. Digitoxin, once central in the management of heart failure and atrial fibrillation, lost prominence in clinical practice and in pharmacology curricula with the advent of angiotensin receptor-neprilysin inhibition and sodium-glucose cotransporter 2 inhibitors. Yet, its interaction with the Na+/K+-ATPase extends beyond inotropy,6 functioning as a signalling platform influencing hypertrophy, fibrosis and neurohumoral activation. Recent randomized data suggest that digitoxin may reduce clinically meaningful endpoints in advanced heart failure,7 prompting reconsideration of its position within guideline-directed therapy. Digitoxin exemplifies a recurring theme in pharmacology: Disappearance from routine practice does not necessarily reflect exhaustion of biological relevance. Other agents illustrate persistence rather than rediscovery. Vitamin K antagonists such as phenprocoumon with decades of clinical experience remain indispensable in patients with mechanical heart valves.8 Despite the rise in direct oral anticoagulant prescriptions, they continue to serve as the standard of care in specific indications. When anticoagulation quality is high, outcomes may be comparable to, or in selected contexts even more favourable than, those achieved with newer agents.9 Therapeutic innovation, therefore, does not automatically imply universal superiority. Some cardiovascular agents have almost disappeared from contemporary practice, not because their biological effects were trivial, but because their therapeutic window was narrow, their tolerability limited or their commercial relevance small. Quinidine, once foundational in rhythm control, is now confined to rare indications.10 Hydralazine survives in contemporary practice in specific heart failure combinations11, 12 and management of treatment-resistant hypertension13 or hypertension in pregnancy.14 Amiodarone, with its complex pharmacokinetics and extracardiac toxicities, would certainly face formidable regulatory hurdles if submitted today, yet remains indispensable in refractory ventricular arrhythmias. In these cases, obsolescence is contextual rather than absolute. At times, we lose important tools entirely. Trimethaphan, a short-acting ganglionic nicotinic receptor antagonist formerly used to induce controlled hypotension, provided a uniquely precise method to interrupt autonomic transmission. Ganglionic blockade allowed quantification of autonomic support of blood pressure and exploration of baroreflex function under controlled conditions.15, 16 As its therapeutic indications dwindled and commercial incentives vanished, trimethaphan disappeared from the market. With it, a powerful instrument for mechanism-oriented experimentation in human integrative physiology was lost. The notion of a cardiovascular drug sanctuary is, therefore, not an appeal to nostalgia, but a proposal for structured preservation and systematic reappraisal. Many older agents were introduced before contemporary standards of phenotyping, imaging and molecular characterization. Their trials often lacked the precision now expected. Re-examined with modern methodologies, some may reveal context-dependent benefits that were previously obscured. Why should clinical pharmacology concern itself with drugs that might not pass today's approval filters? Established agents serve as mechanistic anchors; they shaped our understanding of ion transport, neurohumoral regulation, inflammation and coagulation. They also provide therapeutic resilience where cost and availability limit access to newer compounds. Finally, systematic re-evaluation may identify subgroups in which traditional agents retain relevance. We have, for example, applied peripheral sympatholytic agents such as guanadrel or guanethidine, obsolete in garden variety hypertension, to attenuate neurogenic blood pressure surges in patients with afferent baroreflex failure.17 Suffice it to say that these drugs are no longer available. The COLCAD trial,3 despite its neutral findings, does not close the chapter on colchicine in structural heart disease but sharpens the question. In patients with low inflammatory burden and optimized therapy, broad anti-inflammatory modulation may simply be insufficient. Innovation drives medicine forward. Yet when drugs vanish entirely, we risk losing not only treatment options but experimental instruments and conceptual frameworks. Whether a cardiovascular drug sanctuary is romanticism or necessity is ultimately a matter of perspective. But if clinical pharmacology confines itself to the new, it may inadvertently narrow its own intellectual horizon. LK has no confict of interest, JJ served as advisor for Theravance. Not applicable.