Compliance with Fluvastatin Treatment Characterization of the Noncompliant Population within a Population of 3845 Patients with Hyperlipidemia

doi:10.1016/S0895-4356(99)00019-0

Journal of Clinical Epidemiology

Volume 52, Issue 6, June 1999, Pages 589-594

https://doi.org/10.1016/S0895-4356(99)00019-0 Get rights and content

Abstract

The objectives of the study were to analyze 1) compliance with an HMG-CoA reductase inhibitor, 2) the relationship between treatment compliance and sociodemographic, clinical, and psychological criteria, and 3) the effect of raising patients’ awareness through distribution of an information notice. The results analyzed in this article compare the noncompliant and compliant population independently of awareness. This open-label study was conducted in two randomized parallel groups: a control group that received the information normally given by the practitioners, and an awareness group that received specific informational brochures on diet and cardiovascular risk factors and the reasons for the treatment. Male and female patients (n = 3845) aged 18 to 75 years with primary hypercholesterolemia (type IIa and IIb), not taking a cholesterol-lowering drug or for whom an ongoing treatment was poorly tolerated or ineffective, were to be included. Cholesterol levels had to be greater than 250 mg/dL (or 200 mg/dL if previous coronary history) and triglyceride levels less than 350 mg/dL. A total of 2888 subjects (75%) were defined as compliant (taking more than 90% of the prescription) and 957 (25%) noncompliant. Both populations are identical for age, sex ratio, and different risk factors, with the exception of diabetes. The adverse effects in noncompliant subjects were very clearly different, with an overrepresentation of gastrointestinal and neurologic effects and the noncompliant patients more frequently having more than one adverse effect. Noncompliant patients had an identical duration of follow-up, and the number of patients claiming to have a symptom related to hypercholesterolemia, self-evaluation of cardiovascular risk level, and source of knowledge about cholesterol and diet was similar in both groups. In contrast, in the noncompliant group, there were a larger number of symptomatic patients who thought the drug did not improve the symptoms. In practice, these results show that physicians should systematically evaluate compliance by looking for and analyzing adverse effects and by reassuring the patient when these effects are minor or probably unrelated to the treatment. Diabetics and polymedicated patients deserve special attention in this regard.

Introduction

Hypercholesterolemia, together with smoking hypertension, and diabetes, is one of the four major cardiovascular risk factors. Treatment of hyperlipidemia has proved to be effective as primary and secondary prevention in both diet-based and drug-based trials 1, 2, 3, 4, 5, 6. Nevertheless, in practice the treatment of hyperlipidemia is more difficult owing to problems of compliance with the diet and, more generally, long-term maintenance of the cholesterol-lowering treatment. A double-blind primary prevention trial with pravastatin (placebo vs. pravastatin 40 mg) in 6595 myocardial infarction–free males showed a highly significant decrease in coronary deaths and nonfatal infarctions combined and a reduction in overall mortality [1]. About one third of the patients in this study had stopped taking their treatment by the 5-year mark; these treatment discontinuations occurred progressively during the trial but more rapidly at the outset. The Helsinki Heart Study [4] reported similar results with a significant 34% reduction in ischemic heart disease under gemfibrozil therapy. During the first year of this trial, the proportion of noncompliant patients (defined as those taking less than 75% of the prescribed dose was 15.6% in the treated group versus 23.5% at study termination [7].

This noncompliance resulted in an underestimation of the therapeutic benefits of the treatment. Indeed, in the Lipid Research Clinic Primary Prevention Trial (1900 males taking placebo and 1906 taking cholestyramine), the incidence of myocardial infarction decreased by 19% in the treated group, and there was a further twofold reduction in coronary morbidity in the compliant group [3].

Noncompliance is a complex phenomenon in which the characteristics of the treatment, the patient, the physician, and the disease all play a role. Good tolerability of cholesterol-lowering drugs does not lead to better compliance, as illustrated in the WOSCOPS study [1], in which the overall frequency of treatment discontinuations was identical in subjects taking placebo and active treatment. This was also observed in the Helsinki study, in which the proportion of noncompliant patients was 15.6% and 16.7% in the treatment and placebo groups, respectively, the first year and 23.5% and 20.8%, respectively, at the end of the study.

The extent of this practical problem, as demonstrated in three primary prevention trials with three different types of drugs, contrasts with the scarcity of the scientific literature on noncompliance with cholesterol-lowering treatments. In fact, few studies are designed to analyze the causes of noncompliance, of which there are potentially many [9]. Although it is impossible to achieve a full understanding of the causes of poor compliance in a single study, we have performed a practical analysis of the frequency of noncompliance in patients consulting private practitioners for hyperlipidemia and for whom fluvastatin treatment was prescribed. This study had two main objects: 1) to analyze the relationship between treatment compliance and the characteristics of a large patient population, and 2) to analyze the effect of raising patients’ awareness through distribution of an information notice about the treatment. Only the results concerning the first objective are presented here; the others will be presented in a separate article.

Section snippets

Study Design

This French multicenter open-label study was conducted in two randomized parallel groups: a control group that received the information normally given by the practitioners, and an awareness group that received specific informational brochures on diet and cardiovascular risk factors and the reasons for the treatment.

Study Objectives

The study was designed to fulfil two main objects: 1) to analyze the relationship between treatment compliance and sociodemographic, clinical, and psychological criteria, and 2) to

General Characteristics of the Two Populations

A total of 4813 patients seen by a practitioner received a prescription for fluvastatin 40 mg taken as a single evening dose. A total of 4632 (96.2%) of these patients were evaluable, and compliance was determined for 3845 patients, or 83% of the population, because 787 patients (17%) did not return their blister packs. Patients who did not return their blister packs did not differ from those who did with respect to age, sex ratio, body mass index (BMI), smoking status, and frequency of

Discussion

The value of treating hypercholesterolemia is now well established. Treatment lowers mortality and the incidence of cardiovascular events. Yet a major problem with such primary and secondary prevention is that it is a long-term treatment in a population that usually is clinically asymptomatic.

The HMG-CoA reductase inhibitor fluvastatin, at the dose of 40 mg, has proved to be an effective and safe cholesterol-lowering drug [9]. More recently, this drug has been shown to be beneficial in coronary

Acknowledgements

The study was supported by research grants from Novartis Pharma SA.

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A major drawback in the medication adherence literature today is the absence of a gold standard for measuring medication adherence. Objective measures of nonadherence such as prescription claims and pill count, while quantifying nonadherence, do not provide the reasons for nonadherence, hence making it difficult to develop intervention strategies. Self-reported measures are helpful to determine reasons for nonadherence; however, widely used self-reported measures such as the Morisky scale are restricted to only few potential reasons.
The objective of this study was to develop a new scale to measure self-reported nonadherence and to compare it with the existing Morisky scale.
A cross-sectional study of adult U.S. population on cholesterol-lowering and asthma maintenance medications was used. Data on nonadherence were collected using (1) the newly developed Medication Adherence Reasons Scale (MARS), (2) Morisky scale, and (3) an objective self-reported measure.
A total of 840 responses were collected. Factor analysis of MARS resulted in 5 subscales in cholesterol-lowering medications and 3 subscales in asthma maintenance medications. The level of agreement between both scales in identifying adherents and nonadherents as measured by kappa coefficient was 0.381 in cholesterol-lowering medications and 0.545 in asthma medications. MARS was able to identify various other significant reasons for nonadherence than that identified by the Morisky scale.
A new subjective measure of medication nonadherence based on the frequently reported reasons of nonadherence was developed, and it showed adequate reliability when compared with the Morisky scale to warrant future study.
Dietary modulators of statin efficacy in cardiovascular disease and cognition
2014, Molecular Aspects of Medicine
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In that study, 25OHD concentrations declined slightly over the course of the observation period. Despite the proven efficacy of statin therapy, it is met with side effects which decrease prescription adherence (Bruckert et al., 1999). Myalgia (general muscle pain) is the most common side effect and its risk is dose-dependent (Ucar et al., 2000).
Cardiovascular disease remains the leading cause of morbidity and mortality in the United States and other developed countries, and is fast growing in developing countries, particularly as life expectancy in all parts of the world increases. Current recommendations for the prevention of cardiovascular disease issued jointly from the American Academy of Cardiology and American Heart Association emphasize that lifestyle modification should be incorporated into any treatment plan, including those on statin drugs. However, there is a dearth of data on the interaction between diet and statins with respect to additive, complementary or antagonistic effects. This review collates the available data on the interaction of statins and dietary patterns, cognition, genetics and individual nutrients, including vitamin D, niacin, omega-3 fatty acids, fiber, phytochemicals (polyphenols and stanols) and alcohol. Of note, although the available data is summarized, the scope is limited, conflicting and disparate. In some cases it is likely there is unrecognized synergism. Virtually no data are available describing the interactions of statins with dietary components or dietary pattern in subgroups of the population, particularly those who may benefit most were positive effects identified. Hence, it is virtually impossible to draw any firm conclusions at this time. Nevertheless, this area is important because were the effects of statins and diet additive or synergistic harnessing the effect could potentially lead to the use of a lower intensity statin or dose.
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These studies included a total of 2,663,638 patients (sample size range 83-962,877), and average adherence in all studies was 48%. Among the 53 included studies, 51 evaluated adherence based on gender8,9,17,19-66 and 11 based on race.8,20,21,33,41-43,47,65,67,68 The maximum duration of follow-up ranged from 3 to 156 months (average 39 months).
Significant disparities exist in cardiovascular outcomes based on race/ethnicity and gender. Rates of evidence-based medication use and long-term medication adherence also appear to be lower in racial subgroups and women but have been subject to little attention. Our objective was to evaluate the effect of race/ethnicity and gender on adherence to statin therapy for primary or secondary prevention.
Studies were identified through a systematic search of MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Database of Systematic Reviews (through April 1, 2010) and manual examination of references in selected articles. Studies reporting on adherence to statins by men and women or patients of white and nonwhite race were included. Information on study design, adherence measurement, duration, geographic location, sample size, and patient demographics was extracted using a standardized protocol. From 3,022 potentially relevant publications, 53 studies were included. Compared with men, women had a 10% greater odds of nonadherence (odds ratio 1.10, 95% confidence interval [CI], 1.07-1.13). Nonwhite race patients had a 53% greater odds of nonadherence than white race patients (odds ratio 1.53, 95% CI 1.25-1.87). There was significant heterogeneity in the pooled estimate for gender (I² 0.95, P value for heterogeneity <.001) and race (I² 0.98, P value for heterogeneity <.001). The overall results remained unchanged in those subgroups that had significantly less heterogeneity.
Among patients prescribed statins, women and nonwhite patients are at increased risk for nonadherence. Further research is needed to identify interventions best suited to improve adherence in these populations.
Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): A randomised, double-blind, placebo-controlled, phase 2 study
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Statin-related muscle complications typically involve myalgias with little or no increase in creatine kinase activity. Although this level of myopathy does not necessitate discontinuation of statins, it often leads to non-compliance.20 The estimated incidence of more serious statin-related muscle complications such as myositis or rhabdomyolysis (creatine kinase activity >ten times ULN) with clinical sequelae including renal injury is about one in 3400 statin users.21
Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment.
In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18–75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777.
406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg −41·0% [95% CI −46·2 to −35·8]; 105 mg −43·9% [–49·0 to −38·7]; 140 mg −50·9% [–56·2 to −45·7]; every 4 weeks AMG 145 280 mg −39·0% [–44·1 to −34·0]; 350 mg −43·2% [–48·3 to −38·1]; 420 mg −48·0% [–53·1 to −42·9]; placebo every 2 weeks −3·7% [–9·0 to 1·6]; placebo every 4 weeks 4·5% [–0·7 to 9·8]; and ezetimibe −14·7% [–18·6 to −10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported.
The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance.
Amgen.
Toward "pain-free" statin prescribing: Clinical algorithm for diagnosis and management of myalgia
2008, Mayo Clinic Proceedings
Citation Excerpt :
The incidence of myalgia, which is not as well defined as that of more serious myotoxicities, is reported in randomized controlled trials (RCTs) as ranging from 1.5% to 3.0%.31,32 However, in clinical practice, up to 10% of outpatients receiving statins report muscle pain.22,34–38 The higher rate in clinical practice reflects the tendency to exclude from RCTs potentially statin-intolerant patients and those with risk factors for muscle toxicity (eg, elderly patients, those receiving polypharmacy, individuals with renal or hepatic impairment).25,39
Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.
Therapeutic compliance: A prospective analysis of various factors involved in the adherence rate in type 2 diabetes
2006, Diabetes and Metabolism
It's established that adherence rates to treatment are bad in chronic illnesses. The number of medicines prescribed and the rates of daily dosages have been shown to be of major influence for therapeutic compliance in AIDS or hypertension. Nevertheless, data on adherence to prescribed medications amongst diabetics are scarce. The aim of our study was to evaluate parameters influencing therapeutic compliance in type 2 diabetes. Adherence to treatment was evaluated by a questionnaire filled out during patient's hospitalisation in the diabetology department of a French general hospital of 450 beds. Factors influencing compliance were quantified taking into account demographic characteristics of our population, the treatments used, biological and medical data. 94 patients hospitalised for uncontrolled diabetes, aged 41-89 years, were studied. Non-adherence rate was high, 33 of them showed poor adherence to their drug treatment. Non-compliers were younger than compliant patients (56.512.1 vs. 65.512.5 years old; P<0.0001) and with a lower social position. Clinically, they were characterised by a shorter duration of diabetes and a lower number of clinical complications as macroangiopathy (6.9 vs. 33.3%; P=0.006). The number of daily doses or medicines didn't affect adherence rate. Improved control in therapeutic compliance may lead to better diabetic patients education. The implication is that instead of increasing the dose, changing the medication, or adding a second drug when glucose and HbA_1clevels are high, clinicians should consider counselling patients on how to improve therapeutic compliance.
Observance thérapeutique: analyse prospective des différents facteurs impliqués dans l'observance du traitement du diabète de type 2
Il est admis que l'observance médicamenteuse est médiocre lors de traitement des maladies chroniques. La détermination des causes de non observance chez le patient diabétique est d'une aide précieuse pour optimiser sa prise en charge thérapeutique. Le but de notre étude était de déterminer les différents paramètres influençant l'observance médicamenteuse dans le diabète de type 2. L'observance au traitement a été évaluée à l'aide d'un questionnaire spécifique complété pour chaque patient lors de son hospitalisation dans le service de diabétologie d'un hôpital français de 450 lits.
Les facteurs évalués portaient sur des données démographiques de la population, le traitement utilisé, et les données médicales et biologiques. 94 patients hospitalisés pour un diabète non contrôlé, âgés de 41-89 ans ont été étudiés. Le taux de non observance trouvé était élevé, 33 d'entres eux ne suivant pas régulièrement leur traitement. Les patients non observants (PNO) étaient plus jeunes que les patients observants (PO) (56,5 1,1 vs. 65,5 12,5 ans; P < 0,0001) et caractérisés par un niveau social inférieur. Les PNO présentaient une durée de diabète plus courte et moins de complications macroangiographiques (6,9 vs. 33,3 %; P = 0,006). Le nombre de prises quotidiennes de médicaments n'influençait pas l'observance au traitement. L'amélioration du contrôle de l'observance thérapeutique doit permettre une meilleure éducation du patient diabétique. Avant de modifier les posologies d'un médicament, de le changer, ou d'opter pour une escalade thérapeutique lorsque les réponses biologiques au traitement sont mauvaises, les cliniciens doivent s'interroger sur l'observance au traitement.

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^†: The CREOLE study team: Guilmot (Tours, France), E. Eschwege (INSERM, Villejuif, France), J. M. Lecerf (Institut Pasteur, Lille, France), P. Giral (Pitié-Salpêtrère Hospital, Paris, France), and E. Bruckert, principal investigator (Pitié-Salpêtrère Hospital, Paris, France).

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Short communicationCompliance with Fluvastatin Treatment Characterization of the Noncompliant Population within a Population of 3845 Patients with Hyperlipidemia

Abstract

Introduction

Section snippets

Study Design

Study Objectives

General Characteristics of the Two Populations

Discussion

Acknowledgements

Lancet

Am J Cardiol

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

N Engl J Med

The relationship of reduction in incidence of coronary heart disease to cholesterol lowering

JAMA

Helsinki Heart StudyPrimary-prevention trial with gemfibrozil in middle-aged men with dyslipemia. Safety of treatment, changes in risk factors, and incidence in coronary heart disease

N Engl J Med

WHO cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterolMortality follow-up

Lancet

Clofibrate and niacin in coronary heart disease

JAMA

Comparison of the digoxin marker with capsule counting and compliance questionnaire methods for measuring compliance to medication in a clinical trial

Eur Heart J

Short communication
Compliance with Fluvastatin Treatment Characterization of the Noncompliant Population within a Population of 3845 Patients with Hyperlipidemia