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LONG-TERM COMPLIANCE WITH PHARMACOTHERAPY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION AND CHRONIC HEART FAILURE

Gunnar Gislason  


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Accepted by: Faculty of Health Sciences University of Copenhagen
Defended on: May 16, 2008
Official opponents: Lektor, overlæge, dr.med Gorm Bøje Jensen , Professor, overlæge, dr.med. Mogens Lytken Larsen , Docent, dr.med Niklas Hammar, Sverige
Tutors: Professor, overlæge, dr.med. Christian Torp-Pedersen , Institutleder, cand.stat. Mette Madsen , Overlæge, PhD Steen Z. Abildstrøm

Published in the PhD Database: June 12, 2008


English abstract
During the last 10-15 years new treatment opportunities have improved the survival for patients with cardiovascular disease. Although treatment strategies recommend therapy, there has been increased awareness of undertreatment of cardiovascular disease, especially among subgroups of patients. Therefore, this thesis analysed the nature of undertreatment and long-term compliance in patients with acute myocardial infarction (MI) and chronic heart failure (HF), in order to identify potential areas for future interventions. The thesis had the following objectives: 1) to analyze initiation of treatment with beta-blockers, ACE inhibitors and statins in patients discharged after first hospitalization with acute myocardial infarction during 1995-2002; 2) to analyze initiation of treatment with beta-blockers, ACE inhibitors, statins and spironolactone in patients discharged after first hospitalization with heart failure during 1995-2004; 3) to analyze long-term compliance with beta-blockers, ACE inhibitors and statins in patients with acute myocardial infarction and additionally spironolactone in patients with chronic heart failure; and 4) to analyze association of poor compliance with pharmacological treatment and mortality in chronic heart failure.
A total of 55,315 patients with MI and 107,092 patients with HF hospitalized for the first time were identified in the Danish National Patient Registry and included in the studies. Treatment initiation with beta-blockers, ACE inhibitors, statins, and additionally spironolactone in patients with HF, after discharge was established in the Danish Registry of Medicinal Product Statistics. All subsequent prescriptions dispensed from pharmacies were identified to determine long-term compliance. Multiple logistic regression models were used to analyze initiation of treatment and Cox proportional-hazard models to analyse long-term compliance and mortality.
This thesis demonstrates substantial increase in the use of beta-blockers and statins post-AMI in Denmark, and a more moderate increase in the use of ACE inhibitors. The increase in beta-blocker use was most prominent among patients presumed to have heart failure, whereas the reverse was true for ACE inhibitors. Especially younger patients (< 65 years) reached high levels of statin use.
For both MI patients and patients with HF early initiation of treatment was associated with good long-term compliance, but if treatment was not initiated shortly after discharge the chance of ever starting treatment was low. Dosages used were in general 50% of recommended target dosages, and were seldom adjusted during long-term treatment. There was general undertreatment of elderly patients, women and patients with diabetes, but older age or comorbidity did not impair long-term compliance. Notably, multiple drug treatment or increased severity of HF was not associated with poorer compliance. After 5 years of treatment 58% of patients with MI and 65% with HF were still receiving beta-blockers, 75% and 82% ACE inhibitors, 79 and 82% statins 56% spironolactone and above 80% statins, respectively. Poor compliance (a break in treatment of at least 90 days) with beta-blockers, ACE inhibitors and statins was associated with higher mortality in patients with HF, with hazard ratios (95% CI) for death of 1.25 (1.19-1.32), 1.37 (1.31-1.42) and 1.88 (1.67-2.12) for respectively beta-blockers, ACE inhibitors and statins.
To conclude, this thesis demonstrates that long-term drug compliance was good once medication was started in patients with MI and HF, but treatment dosages were far below recommended dosages. Increased number of concomitant medications or increased severity of did not worsen compliance, but poor compliance was associated with increased mortality. Focus on early treatment initiation, reaching appropriate dosages and long-term compliance is likely to provide long-term benefits.



Danish abstract
I de sidste 10-15 år har nye behandlingsmuligheder øget overlevelsen for hjertepatienter. Selvom kliniske guidelines anbefaler behandling, har der været stigende erkendelse af at nogle patientgrupper bliver underbehandlet / har dårlig kompliance og derfor ikke får det fulde udbytte af de nye behandlingsmuligheder. I denne afhandling fokuseres på baggrunden for underbehandling samt analyser af langtidskompliance med farmakologisk behandling hos patienter med akut myokardieinfarkt (AMI) og kronisk hjertesvigt (HF). Afhandlingen har følgende formål: 1) at analysere opstart af behandling med betablokker, ACE hæmmer og statin hos patienter indlagt med AMI i perioden 1995-2002; 2) at analysere opstart af behandling med betablokker, ACE hæmmer, statin og spironolacton hos patienter indlagt med HF i perioden 1995-2004; 3) at analysere langtidskompliance med betablokker, ACE hæmmer og statin hos patienter med AMI og yderligere spironolacton hos patienter med HF; og 4) at undersøge relationen mellem dårlig kompliance og mortalitet hos patienter med kronisk hjertesvigt.
I alt 55.315 patienter med AMI og 107.092 patienter med HF blev identificeret i Landspatientregistret og inkluderet i analyserne. Opstart af behandling med betablokker, ACE hæmmer, statin og spironolacton blev identificeret i Lægemiddelstatistikregistret og alle efterfølgende receptindløsninger blev fulgt for at belyse langtidskompliance. Multiple logistiske regressions modeller blev anvendt ved analyser af opstart af behandling og Cox proportional-hazard modeller ved analyser af langtidskompliance og mortalitet.
Der var betydelig øgning i brug af betablokker og statin post-AMI i Danmark, men mere moderat øgning i brug af ACE hæmmer. Øgningen i betablokker forbruget var mest tydelig hos patienter med HF, men det forholdt sig omvendt for ACE hæmmer. Der var især højt forbrug af statiner hos yngre patienter (< 65 år). Der var generel underbehandling af kvinder, ældre patienter og patienter med diabetes.
For både patienter med AMI og HF var tidlig opstart af behandling forbundet med god langtidskompliance. Hvis behandling ikke var opstartet tidligt efter udskrivelsen var sandsynligheden lille for at patienten opstartede behandling på et senere tidspunkt. De doser der blev anvendt var 50% af anbefalet dosis og doser blev sjældent justeret i forbindelse med langtidsbehandling. Der var generel underbehandling af ældre patienter, kvinder og patienter med diabetes, men høj alder, komorbiditet eller behandling med flere præparater samtidigt forværrede ikke langtidskompliance. Efter 5 år fra start af behandling modtog henholdsvis 60-65% af patienter stadig betablokker behandling, 75-80% ACE hæmmer, 56% spironolacton og 80% statin behandling. Dårlig kompliance (over 90 dages pause i behandling) med betablokker, ACE hæmmer og statin var forbundet med øget mortalitet, med hazard ratio for død (95% sikkerhedsgrænser) på henholdsvis 1,25 (1,19-1,32), 1,37 (1,31-1,42) og 1,88 (1,67-2,12) for betablokker, ACE hæmmer og statin.
Afhandlingen har vist høj langtidskompliance med farmakologisk behandling hos patienter med AMI og HF, hvis behandlingen var igangsat tidligt efter udskrivelse, men anvendte behandlingsdoser var langt under anbefalede slutdoser. Behandling med flere typer medicin samtidigt eller øget sværhedsgrad forværrede ikke kompliance, men dårlig kompliance var forbundet med øget mortalitet blandt HF patienter. Fokus på tidligt opstart af medicinsk behandling, optitrering til anbefalede slutdoser og langtidskompliance, vil fremme langtidsresultater og prognose.