Ehi705 1153.1158

European Heart Journal (2006) 27, 1153–1158 Long-term compliance with beta-blockers,angiotensin-converting enzyme inhibitors,and statins after acute myocardial infarction Gunnar H. Gislason1,2*, Jeppe N. Rasmussen2, Steen Z. Abildstrøm2,3, Niels Gadsbøll4,Pernille Buch1,2, Jens Friberg1, Søren Rasmussen2, Lars Køber5, Steen Stender6, Mette Madsen2,and Christian Torp-Pedersen1 1 Department of Cardiovascular Medicine, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV,Denmark; 2 National Institute of Public Health, Copenhagen, Denmark; 3 Department of Cardiology, Gentofte UniversityHospital, Hellerup, Denmark; 4 Department of Internal Medicine, Roskilde County Hospital, Roskilde, Denmark; 5 Departmentof Cardiology, The Heart Centre, Rigshospitalet—National University Hospital, Copenhagen, Denmark; and6 Clinical Biochemistry, Gentofte University Hospital, Hellerup, Denmark Received 10 October 2005; revised 5 December 2005; accepted 8 December 2005; online publish-ahead-of-print 6 January 2006 Aims To study initiation, dosages, and compliance with beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors, and statins in patients after acute myocardial infarction (AMI) and to identify likely Methods and results Patients admitted with first AMI between 1995 and 2002 were identified by linking nationwide administrative registers. A total of 55 315 patients survived 30 days after discharge and were included; 58.3% received beta-blockers, 29.1% ACE-inhibitors, and 33.5% statins. After 1, 3, and 5 years, 78, 64, and 58% of survivors who had started therapy were still receiving beta-blockers, 86, 78, and 74%were receiving ACE-inhibitors, and 85, 80, and 82% were receiving statins, respectively. Increased ageand female sex were associated with improved compliance. The dosages prescribed were generally 50%or less of the dosages used in clinical trials, and dosages did not increase during the observation period.
Patients who did not start treatment shortly after discharge had a low probability of starting treatmentlater.
Conclusion The main problem with underuse of recommended treatment after AMI is that treatment isnot initiated at an appropriate dosage shortly after AMI. A focused effort in the immediate post-infarctionperiod would appear to provide long-term benefit.
treatment, drug dosages, and long-term compliance withbeta-blockers, ACE-inhibitors, and statins in 71 515 patients after their first AMI between 1995 and 2002.
inhibitors, and statins are recommended for most patientsfollowing an acute myocardial infarction (AMI), but underuseis widely documented.1,2 Underuse may involve not starting therapy, poor compliance, and underdosing. Much attention The National Hospital Registry keeps records on all hospital admis- has focused on the fact that many patients are never sions in Denmark since 1978, and each hospitalization is classified offered treatment,2 but compliance with treatment and according to the International Classification of Diseases (ICD), dosing has received less attention. Comprehensive analyses until 1994 the ICD-8 and from 1994 the ICD-10. All patients are regis- of initiation, compliance, and dosing are necessary to learn tered via a unique and permanent civil registration number. The the likely targets for improving long-term use. Since 1995, Danish Registry of Medicinal Product Statistics includes information the Danish Registry of Medicinal Product Statistics has regis- about all prescription medicines dispensed from pharmacies in tered all prescriptions dispensed from pharmacies in Denmark since 1995. All prescriptions are registered at an individuallevel by using the civil registration number. The Registry classifies Denmark according to each patient’s unique civil registration medicines according to the Anatomical Therapeutic Chemical number. In this study, we linked data from this Registry with (ATC) system, an international classification system of pharmaceuti- data from the National Hospital Registry to study initiation of cals. As all residents in Denmark are covered by a national healthsecurity system and get the cost of drugs partly reimbursed, allpharmacies are required by law to register all prescription * Corresponding author. Tel: þ45 3531 3328; fax: þ45 3975 1803.
dispensed in this nationwide registry.
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected] All patients aged 30 or older admitted with a diagnosis of first AMI For descriptive statistics, the results are given as mean values with (ICD-10: I21–I22) between 1995 and 2002 and alive 30 days after standard deviation or as median values with range. To analyse discharge (180 days for statins) were identified from the National differences in proportion in drug use and death rates between Hospital Registry. The diagnosis of AMI in the National Hospital 1995 and 2002, we tested for linear trend in logistic regression Registry has been validated and has a sensitivity of 91% and predic- models. The rates of first dispensing of treatment and break in tive value of 93%.3 The selection procedure and characteristics of treatment were estimated by the Kaplan–Meier method. To the patients have been detailed previously.4,5 We registered analyse the effect of available covariates (age, gender, year of whether patients had a prescription of beta-blockers (ATC code AMI, and concomitant medical treatment) on long-term compliance, C07) and ACE-inhibitors (ATC code C09—also including angiotensin we used Cox multivariable proportional hazard models and censor- 2 receptor blockers) dispensed 0–30 days from discharge after ing for death. Model assumptions—the linearity of continuous first AMI and statins (ATC code C10AA) dispensed 0–180 days from variables, the proportional hazard assumption, and lack of discharge. The reason the interval for statins differed was that interaction—were tested and found valid unless otherwise indi- the reimbursement policies for statins changed during the period.
cated. Furthermore, we calculated the persistence of therapy, In 1995, reimbursement required individual application, but after defined as number of patients having medicine available at any 1998, all AMI patients were reimbursed for the full cost of statins time (having filled at least one prescription early after the AMI) without need for individual application.
divided by the number of patients alive within particular treatment All subsequent prescriptions were identified until the end of year group. Patients with missing information or lost to follow-up (emi- 2002 or the date of death. Among patients who did not receive grated), n ¼ 22 (0.04%), were censored at the time of disappear- treatment early after discharge, we identified those who started ance. All statistical calculations were performed using the SAS treatment between 30 days and 1 year to estimate whether a statistical software package, version 8.2 for UNIX servers (SAS significant proportion initiated treatment later. As the registries do not include information of left ventricular function and that theICD-10 cod for heart failure has a relatively low sensitivity, the dispensed prescription of loop diuretics (ATC code C03C) 90 daysbefore to 30 days after discharge was used as a proxy for the The Danish Data Protection Agency approved this study, and data diagnosis of heart failure. In the same way, dispensed prescription were made available to us such that individuals could not be of antidiabetics (ATC code A10) 90 days before to 30 days after discharge was used as a proxy for the diagnosis of diabetesmellitus.
During the 8-year study period, 71 515 patients had a firstadmission for AMI. The 30-day mortality was 22.7%, The Danish Registry of Medicinal Product Statistics includes ranging from 26.0% in 1995 to 17.4% in 2002 (P , 0.001).
information about the dispensing date of the prescription, the A total of 55 315 patients were alive 30 days after discharge strength of the drug, and the total number of tablets dispensed and were included in the analysis of the use of beta-blockers but not the prescribed dose of the drug. The dose of each prescrip- and ACE-inhibitors after AMI. The 48 412 patients who were tion was therefore calculated from the average dose given during alive 180 days after discharge were included in the analysis up to three consecutive prescriptions. Excess tablets wereallowed to be accumulated for up to three previous consecutive of statins. The baseline characteristics of the study popu- prescriptions at any time. On the basis of these assumptions, we calculated whether patients at any time had tablets available Figure 1 illustrates the timing of the first dispensing of or not. We defined a patient as receiving treatment if tablets each of the three drugs during the first year after AMI (cen- sored for death). The probability of starting treatment was To determine long-term compliance, we calculated whether low if treatment was not started early for beta-blockers patients who did not receive treatment were in a break of 7, 30, and ACE-inhibitors. Only 5621 (10.7%) patients started 90, and 180 days or longer. We calculated the proportion of patients beta-blocker treatment and 6694 (12.1%) ACE-inhibitors who restarted therapy after a break of a particular length and found between 31 days and 1 year after AMI. For statins, the that a substantial proportion of patients restarted treatment again start of treatment was slower, but between day 181 and 1 after a break shorter than 90 days. We therefore used a break of atleast 90 days as a proxy for poor compliance.
year, only 2868 (5.9%) patients started therapy. From 1995 To validate the calculations, sensitivity analysis was performed to 2002, the number of patients initiating beta-blocker with the average daily dose calculated also from single prescrip- treatment later than 30 days after the infarction declined tions, with the minimal dose equal to a previously calculated dose from 11.5 to 9.3% (P , 0.001) and statins after 180 days for the same patient and allowing each patient to keep residual declined from 6.7 to 1.7% (P , 0.001), but the number of tablets from one to five prescriptions. The manipulations resulted patients receiving ACE-inhibitors after 30 days increased in 75–85% agreement between the calculated doses and 2–4% with from 10.5 to 12.0% (P , 0.001). Hospital-based physicians changes in the number of patients stopping therapy.
issued the majority of the initial early prescriptions ofbeta-blockers, ACE-inhibitors, and statins (Table 2). The evenly between hospital-based physicians and general We calculated the average dosages of the most frequently used medications within each group by multiplying the strength of the Figure 2 illustrates the long-term compliance for patients formulation by the number of tablets per day. The averagedosage was calculated only for patients who had medication avail- who filled a prescription for a beta-blocker or ACE-inhibitor able for treatment. To estimate underdosing, we compared the within 30 days of AMI or a statin within 6 months. Short average dosage with the dosages used in major randomized clinical breaks in therapy were common, but many patients restarted therapy later (Table 3). We used a break of at Long-term compliance with beta-blockers, ACE-inhibitors, and statins least 90 days to analyse factors of importance for poor Baseline characteristics of the study sample The Cox multivariable proportional hazard analysis (Table 4) revealed that although there were increasing number of patients initiating treatment from 1995 to 2002, this did not affect compliance. On the contrary, com- pliance improved with beta-blockers. Women had better compliance with beta-blockers and statins than men, and older patients had better compliance with beta-blockers but worse compliance with ACE-inhibitors and statins.
Concomitant medical treatment did not worsen compliance, except for patients taking loop diuretics had slightly poorer Table 5 shows the average dosages of the most frequently used beta-blockers, ACE-inhibitors, and statins. We analysed whether dosages changed during the observation time by comparing the average dosages used during the first year of treatment with the average dosages used between 3 and 5 years of treatment. This revealed that the average dosages of beta-blockers and ACE-inhibitors changed only between 2 and 7%. The average dosages of simvastatin and pravastatin changed ,3%, but the dosages for atorvastatin increased 21.5% from the first year when compared with3–5 years of therapy.
SD, standard deviation.
aRanging from 38.1% in 1995 to 67.9% in 2002 (P , 0.001).
bRanging from 24.5% in 1995 to 35.5% in 2002 (P , 0.001).
cRanging from 11.7% in 1995 to 63.0% in 2002 (P , 0.001).
This study has four main findings. (i) If prophylactic treat-ment after a myocardial infarction is not initiated at thetime of discharge, the likelihood of ever receiving treatmentis small. (ii) If treatment is started early post-AMI, mostpatients adhere to treatment Initiation of treatment nearly always relies on the initiativeof the hospital physicians. (iv) The prescribed doses ofall three drugs were substantially lower than thoserecommended and seldom adjusted during long-termtherapy.
All three drugs were prescribed with increasing frequencyduring the study period, the increase being most pro-nounced for beta-blockers and statins. Beta-blockers andACE-inhibitors were primarily initiated during the first 30days after AMI, whereas statin therapy was more graduallyinitiated during the first 6 months (Figure 1). This was prob-ably related to Denmark’s reimbursement policies, whichchanged in 1998, and AMI patients no longer need to apply Cumulative frequency of patients with first AMI who filled a first individually for reimbursement of the cost of statin prescription of beta-blocker, ACE-inhibitor, or statin within 1 year afterdischarge (censored for death).
therapy. Notably, the vast majority of early prescriptions First prescription claim of beta-blockers, ACE-inhibitors, and statins dispensed 0–30 days and 31–365 days from discharge, accord- ing to the type of the physician issuing the prescription were written by hospital-based physicians, whereas general practitioners initiated very few early prescriptions (Table 2).
After 5 years of treatment, 58% of patients were still receiv- The relatively few patients who started late had a more ing beta-blockers, 74% ACE-inhibitors, and 82% statins even contribution by hospital-based physicians and general (Figure 2). The literature is sparse regarding studies on practitioners, but the general practitioners still only long-term compliance with treatment post-AMI. Registries accounted for about half the initial prescriptions. Further, that included selected departments have shown 6-month the number of patients initiating treatment later than 30 compliance with ACE-inhibitors and beta-blockers exceed- days for beta-blockers and 180 days for statins from 1995 ing 80%.2,6 Studies from North America among patients to 2002 declined substantially. This emphasizes the import- older than 65 years of age and patients participating in ance of initiating treatment early, as the probability of specific insurance systems showed that 60–80% continued treatment after 1 year.7 The most comprehensive long- It is interesting that although treatment was mostly initiated by hospital-based physicians, there still remains therapy. The long-term compliance in these studies was substantial proportion of patients who do not start treat- 50–85% after 1 year, 40–77% after 2–3 years, and 45–50% ment. Hospital-based physicians taking care of patients with AMI are most often specialists in internal medicine or The difficulty in comparing these numbers with those in cardiology, and thus should be updated in appropriate treat- our study is that compliance has been defined in many ment of AMI patients. Most likely, some discharging physi- different ways. Previous studies have not distinguished cians rely on the fact that the doctor taking care of the between breaks and discontinuation. Most of our patients AMI patient after discharge initiates appropriate therapy restarted therapy after a break, especially after a brief not already started in the hospital, whereas doctors taking break (Table 3). Even after a break of at least 90 days, care of the patient after discharge depend on the judge- almost half of the patients restarted therapy with beta- ment of the discharging physician. To prevent such misun- blockers and ACE-inhibitors within 1 year and almost 70% derstanding, the discharging physician should initiate treatment in the hospital and if not started at discharge To analyse the factors influencing long-term compliance, give clear message to the doctor taking care of the AMI we used the time to first break of 90 days, or longer, in multivariable proportional hazard analysis (Table 4). The increase in early initiation of treatment during the studyperiod was not associated with decreased long-termcompliance—instead, compliance improved moderately butstatistically significantly. Notably, multiple drug therapydid not reduce compliance, and increased age and femalesex were also associated with improved compliance. Theseresults emphasize that an increased effort during the studyperiod to initiate more medicines in more patients was notassociated with worse compliance.
Analysis of the dosages of the most frequently used drugswithin each class revealed substantial underdosing ofalmost all medicines, with dosages generally 50% or lessthan the dosages that randomized trials have proved to beeffective (Table 5).15–19 We also analysed whether dosageschanged from the first prescription dispensed whencompared with later on but found that patients largelystayed at their initial dosage. Defining a target dose forstatins is more difficult because this may be related to the Persistence with therapy in patients who claimed at least one prescription early after AMI. Each point represents number of patients with effect on serum cholesterol levels. Our data do not cover available medication divided by the number of patients alive at that time.
patients’ cholesterol levels, and thus we cannot conclude The proportion of AMI patients on beta-blocker, ACE-inhibitor, or statin therapy who experienced a break of at least 7, 30, 90, or 180 days within 5 years of treatment and the proportion who had re-initiated therapy within 1 year Proportion re-initiating treatment within 1 year Long-term compliance with beta-blockers, ACE-inhibitors, and statins Cox multivariable proportional hazard analysis of covariates predicting first break in therapy of more than 90 days (a proxy for low compliance) with beta-blockers, ACE-inhibitors, and statins in patients with first AMI, 1995–2002 RR, relative risk; CI, confidence interval.
a1995–96 as reference.
bWomen as reference.
cAged 30–59 as reference.
dNon-users as reference.
Average daily dosage of the most frequently used beta-blockers, ACE-inhibitors, and statins after AMI The AMI diagnosis in the National Hospital Registry has beenvalidated and is sensitive as well as specific.3 The registry includes all hospital admissions in Denmark from 1978 and therefore not affected by selection bias by only includingselected hospitals, certain health insurance systems, or age groups. A comprehensive accumulation of nationwide admission data and linking to other registries is unique for Denmark. Although the study is based on registries from a single country, Denmark’s health insurance system, which partly reimburses all patients for drug expenses, is typical A break in therapy of at least 90 days was arbitrarily selected to define long-term compliance, as one-third to half of the population experienced break of at least 90 days. Analyses of the effects of shorter or longer breaks in therapy did not change the results noticeably.
The diagnostic criteria for AMI changed in 1999, and during the study period more sensitive diagnostic markers have been introduced (i.e. troponins). Nevertheless, this has not resulted in dramatic change in the prognosis of AMI 24 and it is unlikely that this affects our study.
aThe most frequently used medications within each class.
bProportion of all medications used within each class.
c information about basal clinical variables such as location Dosages used in randomized clinical trials with clinical endpoint or size of infarction, smoking status, systolic function, and co-morbidity. However, the indication for treatment withbeta-blocker or statin after AMI is independent of these about the dosages of statins. Although not as prominent as factors. Further, ACE-inhibitors are primarily indicated for for beta-blockers and ACE-inhibitors, the dosages of statins patients with reduced systolic function and diabetes. We were generally lower than those used in randomized therefore used the concomitant use of loop diuretics and antidiabetics as a proxy for, respectively, heart failure and diabetes, to define subgroups of patients where there enzyme inhibitors after myocardial infarction in Denmark, 1995–2002.
was definite indication for treatment. The registries do not 5. Rasmussen J, Gislason G, Abildstrom S, Rasmussen S, Gustafsson I, Buch P, include information about contraindications to treatment, Friberg J, Køber L, Torp-Pedersen C, Madsen M, Stender S. Statin use adverse reactions, or allergies that might have caused the after acute myocardial infarction: a Danish nationwide study. Br J Clin treatment not to start or to be terminated early after start. Also, we do not know how many patients started 6. Eagle KA, Kline-Rogers E, Goodman SG, Gurfinkel EP, Avezum A, Flather MD, treatment in hospital and did not continue treatment after Granger CB, Erickson S, White K, Steg PG. Adherence to evidence-basedtherapies after discharge for acute coronary syndromes: an ongoing discharge. Furthermore, factors such as race/ethnicity, prospective, observational study. Am J Med 2004;117:73–81.
history of depression or other psychiatric illness, and the 7. Simpson E, Beck C, Richard H, Eisenberg MJ, Pilote L. Drug prescriptions specialty of the physician taking care of patient could also after acute myocardial infarction: dosage, compliance, and persistence.
8. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 9. Muhlestein JB, Horne BD, Bair TL, Li Q, Madsen TE, Pearson RR, Anderson JL.
This study demonstrates that long-term compliance can be Usefulness of in-hospital prescription of statin agents after angiographic expected if treatment with beta-blockers, ACE-inhibitors, diagnosis of coronary artery disease in improving continued compliance and statins is started early after AMI, although dosages are and reduced mortality. Am J Cardiol 2001;87:257–261.
seldom uptitrated during long-term therapy. In contrast, if 10. Larsen J, Andersen M, Kragstrup J, Gram LF. High persistence of statin use in a Danish population: compliance study 1993–1998. Br J Clin Pharmacol therapy is not started in the early phase after AMI, the patient is unlikely to ever receive appropriate medical 11. Andrade SE, Walker AM, Gottlieb LK, Hollenberg NK, Testa MA, treatment. Most general practitioners and other physicians Saperia GM, Platt R. Discontinuation of antihyperlipidemic drugs—do treating survivors of AMI seem to rely on the initiative and rates reported in clinical trials reflect rates in primary care settings? judgement of the hospital department from which the 12. Avorn J, Monette J, Lacour A, Bohn RL, Monane M, Mogun H, LeLorier J.
patient is discharged. This underscores the importance of Persistence of use of lipid-lowering medications: a cross-national study.
therapy in survivors of AMI. A more focused effort from 13. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J.
hospitals treating AMI patients in starting these patients Long-term persistence in use of statin therapy in elderly patients.
JAMA 2002;288:455–461.
on relevant medicines and titrating them to an effective 14. Kopjar B, Sales AE, Pineros SL, Sun H, Li YF, Hedeen AN. Adherence with dose will result in long-term benefits.
statin therapy in secondary prevention of coronary heart disease in veter-ans administration male population. Am J Cardiol 2003;92:1106–1108.
15. Reiter MJ. Cardiovascular drug class specificity: beta-blockers. Prog 16. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, The study was supported by an unrestricted research grant from the Videbaek J, Cole DS, Auclert L, Pauly NC. A clinical trial of the angiotensin- Danish Pharmaceutical Association (Grant no. 31-03) and the Danish converting-enzyme inhibitor trandolapril in patients with left ventricular Heart Foundation (Grant no. 05-04-B46-A522-22207).
dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation(TRACE) Study Group. N Engl J Med 1995;333:1670–1676.
17. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The AcuteInfarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993; The study sponsors had no involvement in study design; in the collection, analysis, and interpretation of data; in the 18. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, writing of the report; and in the decision to submit the Geltman EM, Goldman S, Flaker GC. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardialinfarction. Results of the survival and ventricular enlargement trial.
The SAVE Investigators. N Engl J Med 1992;327:669–677.
Conflict of interest: several of the authors have given industry- 19. Effect of enalapril on survival in patients with reduced left ventricular sponsored lectures and taken part in clinical trials sponsored by the industry, but there are no specific conflicts of interest related Investigators. N Engl J Med 1991;325:293–302.
20. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet1994;344:1383–1389.
21. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The 1. EUROASPIRE. A European Society of Cardiology survey of secondary effect of pravastatin on coronary events after myocardial infarction in prevention of coronary heart disease: principal results. EUROASPIRE patients with average cholesterol levels. Cholesterol and Recurrent Study Group. European Action on Secondary Prevention through Events Trial investigators. N Engl J Med 1996;335:1001–1009.
Intervention to Reduce Events. Eur Heart J 1997;18:1569–1582.
22. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, 2. Lifestyle and risk factor management and use of drug therapies in coro- Joyal SV, Hill KA, Pfeffer MA, Skene AM, the Pravastatin or Atorvastatin nary patients from 15 countries; principal results from EUROASPIRE II Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction Euro Heart Survey Programme. Eur Heart J 2001;22:554–572.
22 Investigators. Comparison of intensive and moderate lipid lowering 3. Madsen M, Davidsen M, Rasmussen S, Abildstrom SZ, Osler M. The validity with statins after acute coronary syndromes. N Engl J Med 2004; of the diagnosis of acute myocardial infarction in routine statistics: a comparison of mortality and hospital discharge data with the Danish 23. Ess SM, Schneeweiss S, Szucs TD. European healthcare policies for MONICA registry. J Clin Epidemiol 2003;56:124–130.
controlling drug expenditure. Pharmacoeconomics 2003;21:89–103.
4. Gislason G, Abildstrom S, Rasmussen J, Rasmussen S, Buch P, Gustafsson I, 24. Abildstrom SZ, Rasmussen S, Madsen M. Changes in hospitalization rate Friberg J, Gadsbøll N, Køber L, Stender S, Madsen M, Torp-Pedersen C. Nation- and mortality after acute myocardial infarction in Denmark after wide trends in the prescription of beta-blockers and angiotensin-converting diagnostic criteria and methods changed. Eur Heart J 2005;26:990–995.

Source: http://loader.goernogetforhjertet.dk/files/Internationalt/Long-term_compliance_with_beta-blockers_EHJ.pdf