Factors influencing long-term heart failure mortality in patients with obstructive hypertrophic cardiomyopathy in Western Sweden: probable dose-related protection from beta-blocker therapy

Abstract

ObjectiveIn order to avoid effects of referral bias, we assessed risk factors for disease-related mortality in a geographical cohort of patients with hypertrophic obstructive cardiomyopathy (HOCM), and any therapy effect on survival.MethodsDiagnostic databases in 10 hospitals in the West Götaland Region yielded 251 adult patients with HOCM (128 male, 123 female). Case notes were reviewed for clinical data and ECG and ultrasound findings. Beta-blockers were used in 71.3% of patients from diagnosis (median metoprolol-equivalent dose of 125 mg/day), and at latest follow-up in 86.1%; 121 patients had medical therapy alone, 88 short atrioventricular delay pacing and 42 surgical myectomy. Mean follow-up was 14.4±8.9 (mean±SD) years. Primary endpoint was disease-related death, and secondary endpoint heart failure deaths.ResultsThere were 65 primary endpoint events. Independent risk factors for disease-related death on multivariate Cox hazard regression were: female sex (p=0.005), age at diagnosis (p<0.001), outflow gradient ≥50 mm Hg at diagnosis (p=0.036) and at follow-up (p=0.001). Heart failure caused 62% of deaths, and sudden cardiac death 17%. Late independent predictors of heart failure death were: female sex (p=0.003), outflow gradient ≥50 mm Hg at latest follow-up (p=0.032), verapamil/diltiazem therapy (p=0.012) and coexisting hypertension (p=0.031), but not other comorbidities. Neither myectomy nor pacing modified survival, but early and maintained beta-blocker therapy was associated with dose-dependent reduction in disease-related mortality in the multivariate model (p=0.028), and final dose was also associated with reduced heart failure mortality (p=0.008). Kaplan-Meier survival curves analysed in initial dose bands of 0–74, 75–149 and ≥150 mg metoprolol/day showed 10-year freedom from disease-related deaths of 83.1%, 90.7% and 97.0%, respectively (ptrend=0.00008). Even after successful relief of outflow obstruction by intervention, there was survival benefit of metoprolol doses ≥100 mg/day (p=0.01).ConclusionsIn population-based HOCM cohorts heart failure is a dominant cause of death and on multivariate analysis beta-blocker therapy was associated with a dose-dependent cardioprotective effect on total, disease-related as well as heart failure-related mortality.

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy

“…It is not clear if this could be related to a possible protective effect of septal myectomy in patients with high gradients. 9 , 39 The finding of a positive association of age with SCD risk is consistent with the known higher penetrance of SCD in adolescents and teenagers. 7 The overall lower frequency of SCD in early-onset cases may also be related in part to a lower survival into teenage years because of a higher non-SCD mortality and transplant in early life.…”

What Aspects of Phenotype Determine Risk for Sudden Cardiac Death in Pediatric Hypertrophic Cardiomyopathy?

“…This possible confounding role of beta-blocker therapy and beta-blocker dose is supported by increasing beta-blocker dose being associated with a significant reduction in risk of SCD in multivariate Cox-hazard analysis in a Swedish national cohort [ 19 , 29 ]. A protective effect of beta-blocker therapy on total cardiac mortality has now also been found in several large studies in adult HCM, in the USA, Taiwan and Sweden, confirming that beta-blocker therapy is a plausible confounder [ 42 , 43 , 44 ]. The same confounder could also be responsible for childhood ICD-recipients with LVOTO receiving fewer appropriate shocks [ 37 ].…”

Sudden cardiac death in childhood hypertrophic cardiomyopathy is best predicted by a combination of electrocardiogram risk‐score and HCMRisk‐Kids score

“…There are no official guidelines for specific medical therapy in high‐risk patients. Our data suggest that it is worth establishing effective medical therapy with beta‐blocker dose sufficient to achieve good beta‐blockade on exercise testing in all high‐risk patients, even if asymptomatic, because of the risk‐modifying effects seen in our multivariate analysis, and recently reported beneficial effects on all‐cause cardiac mortality 24,25 . Similarly, complete control of outflow‐tract obstruction, if necessary by addition of disopyramide (or myectomy if medical therapy insufficient), should be attempted (see above).…”

“…Our data suggest that it is worth establishing effective medical therapy with beta-blocker dose sufficient to achieve good beta-blockade on exercise testing in all high-risk patients, even if asymptomatic, because of the risk-modifying effects seen in our multivariate analysis, and recently reported beneficial effects on all-cause cardiac mortality. 24,25 Similarly, complete control of outflow-tract obstruction, if necessary by addition of disopyramide (or myectomy if medical therapy insufficient), should be attempted (see above). It is our experience that high ECG Risk-scores may fall when the patient is on effective therapy, particularly in patients who present with large outflow gradients (Östman-Smith, Fernlund unpublished observations).…”