Lipid lowering treatment patterns and goal attainment in Nordic patients with hyperlipidemia

Abstract

Objectives. Observational studies and surveys have shown that lipid-lowering treatment is not optimal neither with regard to number of patients treated nor with number of patients achieving recommended goals. To address this issue in the Nordic countries, we evaluated the published literature on lipid-lowering therapies in preventive cardiology in this region. Design. Nordic papers published from 2000 throughout 2006 dealing with lipid-lowering management in coronary heart disease prevention were identified. In total, 19 studies were analyzed. Results. Approximately half of the patients are inadequately treated and have not achieved recommended treatment goals of total cholesterol <5.0and LDL-cholesterol <3.0 mmol/L. Statins were prescribed most often in low or medium doses. The predictive factors for treatment were cholesterol level, risk of cardiovascular disease, previous cardiovascular disease, age, and gender. Conclusions. There is a considerable need to improve standards of preventive cardiology. Statins have to be given evidence based to achieve treatment goals according to lipid levels, and higher doses of statins or combination therapy with a statin and a cholesterol absorption inhibitor or niacin is often needed.

• Cholesterol
• lipids
• statins
• cardiovascular disease
• Nordic
• guidelines

A large number of studies have highlighted the benefits of lipid-lowering treatment on cardiovascular risk. The relationship between low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) has been extensively documented, and particularly a reduction in LDL-C provides a clear improvement in CHD events 1–4.

Statins are the agents of choice in the pharmacological management of hyperlipidemia. There is large and ever-increasing evidence in support of their efficacy and low rate of side effects 1–4. As a drug class, they have been shown to reduce the incidence of cardiovascular disease (CVD) by 25–60% and the risk of death from any cause by approximately 30%.

Guidelines issued in 2003 by the Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice suggest that target total cholesterol (TC) levels should be <5.0 mmol/L in general, and <4.5 mmol/L for patients with established CVD, diabetes, or in asymptomatic high risk persons; equivalent levels for LDL-C should be <3.0 mmol/L and <2.5 mmol/L, respectively 1. In high risk subjects, the 2007 European guidelines gives an option of TC <4.0 mmol/L and LDL-C <2.0 mmol/L, if feasible 5. However, despite the established risks of hyperlipidemia, the proven benefits of lipid-lowering therapy, and the widespread use of statins, only few of the patients achieve these recommended treatment goals in practice 6, 7 and CVD prevention is clearly less than optimal. This paper examines population demographics, lipid-lowering patterns, and trends in goal attainment for patients treated with lipid-lowering therapy in the Nordic countries consisting of Denmark, Finland, Iceland, Norway, and Sweden, drawing on data from national as well as multinational studies.

Material and methods

We searched the database PubMed with the help of Center of Knowledge, Odense University Hospital, Denmark. We also reviewed the reference list of all selected articles and contacted lipid experts within the Nordic area to identify articles not included in PubMed.

The following search words were used: Nordic, Scandinavian, Scandinavia, Denmark, Danish, Finland, Finnish, Norway, Norwegian, Sweden, Swedish (#1, 257300 hits), Therapy, Lowering, Modifying, Statins, Statin, Prevention, Control, Intervention, Goals, Goal (#2, 5882777 hits), Myocardial Infarction, Cholesterol, Dyslipidemia, Hyperlipidemia, Hypercholesterolemia, Lipid Disorders (#3, 338439 hits), #1 and #2 and #3 (#4, 4089 hits), #1 and #2 and #3 with publication date from 1 January 2000 to 31 December 2006 (#5, 1468 hits). The search was performed in March 2007.

All abstracts resulting from the PubMed search and otherwise identified were reviewed. From these abstracts 25 full-text articles relevant to the topic were reviewed by two of the authors, and of these 19 met our inclusion criteria which were information about goal attainment, cholesterol values and lipid lowering treatment, published in a peer reviewed journal.

Results

Study characteristics

The 19 studies were diverse in nature, consisting of large multinational studies as well as small local studies, investigations of primary as well as secondary intervention, assessments of the general population as well as patients with diabetes or at high risk of CVD, and different years of study conduction. This diversity made it difficult to compare treatment trends between the Nordic countries. An overview of the 19 studies is presented in Table I; full details can be found in the individual published papers 6–24.

Table I.  Studies included in the analysis of lipid lowering treatment patterns and goal attainment in Nordic countries

Study	Patients (origin)	Patients (n)	Patients (type)	Study objective(s)	Study location	Study date	Published reference	Support/conflict of interest declared
European Action on Secondary Prevention by Intervention to Reduce Events (EUROASPIRE) II	Finland, Sweden	990 (records) 740 (interviews)	With established coronary disease	Through record review & patient interview to determine whether European guidelines are being followed for coronary prevention	Cardiology practices	1999–2000	EURO-ASPIRE II study group 2001^6	ESC through grant from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer
The Northern Sweden MONICA Study	Sweden	8 827	General population	Survey to explore time trends in total cholesterol	N/A	1986–2004	Eliasson et al. 2006^7	Various Independent Swedish Independent Councils and Foundations
Treatment of dyslipidemia in T2DM	Denmark	14 644	T2DM	Register study to evaluate monitoring of cholesterol and use of lipid-lowering treatment in T2DM	Hospital & Primary Care	2000–2002	Kristensen et al. 2006^8	No declaration
Cardiovascular Risk Factors (FINRISK)	Finland	622	On lipid lowering treatment +/- CVD	Survey to evaluate cholesterol goal achievement and influential factors		2002	Alemao et al. 2006^9	Merck & Co/Schering-Plough
Lipid Management and Cholesterol Goal attainment	Norway	3 111	On lipid lowering treatment +/- CVD and/or T2DM	Register study to evaluate cholesterol goal attainment and influential factors	Primary Care	1987–2003	Ose et al. 2006^10	MSD/Schering Plough
Routine management study	Denmark	1 163	With dyslipidemia	Register study to evaluate routine dyslipidemia management practices	Primary Care	1998–2000	Kanstrup et al. 2005^11	No declaration
Association between treatment goals and cardiovascular events	Sweden	4 976	On lipid lowering treatment	Register study to investigate if lack of goal achievement translates into higher risk of cardiovascular events	Primary Care	1993–2001	Lindgren et al. 2005^12	Merck & Co
Gap between guidelines and reality in T2DM	Sweden	17 547 in 1996, 57 119 in 2003	With T2DM	Register study to analyse metabolic risk factor level and goal achievement	N/A	1996–2003	Eliasson et al. 2005^13	No declaration
Quality of lipid-lowering study	Denmark	3 477	With IHD	Register study to evaluate lipid treatment patterns	Hospital & Primary care	1990–1999	Kanstrup et al. 2004^14	No declaration
Oslo Heart Study	Norway	1 404	With CVD and/or diabetes	Assessment of prevalence and factors associated with cholesterol lowering statins	General population	2000-
2001	Tonstad et al. 2004^15	No
Tromsø study	Norway	7 973	With CHD or risk factors	Population-based study to characterize lipid-lowering drug users	General population	2001	Hartz et al. 2001^16	University of Tromsø and Norwegian Institution of Health
Losartan Intervention For Endpoint reduction in hypertension (LIFE)	DenmarkFinland, Iceland, Norway, Sweden	6 397	With hypertension & LVH	Comparison of CV morbidity & mortality with losartan- or atenolol-based therapy; use of lipid-lowering agents at investigator's discretion	Outpatient clinics & General Practice	1995–2001	Kristianson et al. 2003^17	Merck & Co
Evaluation of Secondary Prevention Programme	Sweden	760	With CHD	Survey to evaluate adherence to guidelines for secondary prevention	Hospital and Primary Care	1996	Kahan et al. 2001^18	No
Goal achievement study in statin users	Finland	676	On statin monotherapy	Through office lipid measurements to determine whether European guidelines are being achieved for coronary prevention	Primary care		Strandberg et al. 2001^19	Pfizer Finland
Goal achievement study in statin users	Finland	747	On statin monotherapy	Through office lipid measurements to determine whether European guidelines are being achieved for coronary prevention	Primary care		Strandberg et al. 2006^20	MSD Finland / Schering-Plough Finland
Study of statin use after acute MI	Norway	473	With MI	Retrospective study to assess statin prescribing practices	Hospital out-patients	1995–98	Notø et al. 2001^21	Pfizer
Monitoring and treatment after MI study	Denmark	409	With MI, < 70y	Register study to evaluate lipid lowering treatment according to guidelines	Hospital & Primary Care	1995–1997	Kanstrup et al. 2001^22	Danish Pharmacy Foundation, Danish Medical Research Council, Danish Ministry of Research
Goal achievement study	Norway	3 935	On statin monotherapy	To determine to which extent European lipid guidelines are achieved	Primary care	1999	Svilaas et al. 2000^23	MSD Norway
Secondary prevention study	Norway	707 (1994/951 353 (1996/97)	With atherosclerotic disease	Multipractice survey to examine changing trends in prevention of atherosclerotic disease	Primary care	1994/95 & 1996/97	Svilaas et al. 2000^24	MSD Norway

CVD = cardiovascular disease; LVH = left ventricular hypertrophy; IHD = ischemic heart disease; CHD = coronary heart disease; MI = myocardial infarction; T2DM = type 2 diabetes.

The studies included patients who were already given lipid-lowering therapy as well as those who were treatment naïve. Statins were the most frequently prescribed lipid-lowering agents, with their usage increasing over time. Very few patients were given lipid-lowering drugs in combination.

Lipid levels

At baseline (i.e. first patient assessment), TC and LDL-C levels across the Nordic studies ranged from 4.7 mmol/L 6 to 7.9 mmol/L 23, and from 5.0 mmol/L 10 to 5.7 mmol/L 22, respectively. The serum cholesterol levels showed a gradual decline over time 7, 24. The proportion of patients with hypercholesterolemia at baseline (defined as TC ≥5 mmol/L) ranged from 40.4% 6 to 100.0% 17, despite the fact that many of the patients in the studies had been receiving lipid-lowering medications before inclusion in the study.

Goal attainment

The proportion of patients achieving their lipid treatment goals ranged from 7.8% in Norway during the early 1990s 24, to 50.3% in Finland 1999–2000 6 (Table II). In the LIFE study, the use of lipid-lowering therapy was at the discretion of the investigator. Although statin use increased as the study progressed (6.1% of patients were receiving statins at baseline, 21.9% at study termination), 60–70% of treated patients had not achieved a TC goal of <5.0 mmol/L by the end of the study 17. The Finnish goal achievement study sought to reveal mechanisms leading to poor goal attainment 19. Goal attainment was enhanced if the patient was male, had CHD, or the patient himself appreciated lower cholesterol goal. Furthermore, male physicians seemed to attain goals more often than female physicians, possibly through selecting more powerful statins than their female counterparts. A new survey with similar methodology in 2005 among 747 patients demonstrated an improvement 20. The cholesterol levels had now been reduced as compared to the situation in 2000, but still 56% of patients without and 44% with CHD had their LDL-C level over 2.5 mmol/L, the new stricter goal for high-risk patients. The probability of attaining goal was 1.8-fold (95% confidence interval 1.3–2.5) higher among patients who had newer, more efficient lipid therapy (atorvastatin, rosuvastatin, or statin + ezetimibe combination).

Table II.  Reported rates of patients achieving total cholesterol treatment goal (<5 mmol/L), and statin dosing trends (only those studies reporting data are presented)

		Goal attainment (%)
Study	Country	Overall	With lipid-lowering treatment	No lipid-lowering treatment	Statin prescribing patterns
The Northern Sweden MONICA Study^7	Sweden	25.7 ♂ 38.3 ♀	N/A	N/A	N/A
Treatment of dyslipidemia in T2DM^8	Denmark	N/A	43	34	N/A
Cardiovascular Risk Factors (FINRISK)^9	Finland	N/A	46	N/A	Pravastatin 10 mg or equivalent 13%; simvastatin 10 mg or equivalent 38%; simvastatin 20 mg or equivalent 40%; simvastatin 40 mg or equivalent 8%; simvastatin 80 mg or equivalent 1%.
Lipid Management and Cholesterol Goal attainment^10	Norway	N/A	33	N/A	Average initial dose (1987-2003): simvastatin 18.4 mg; atorvastatin 12.7 mg; pravastatin 26.0 mg; lovastatin 29.5 mg; fluvastatin 36.5 mg. Mean prescribed statin dose 2003: simvastatin 26.7 mg; atorvastatin 18.4 mg; pravastatin 30.7 mg; lovastatin 30.5 mg; fluvastatin 70.1 mg.
Routine management study^11	Denmark	N/A	42.3	N/A	N/A
Association between treatment goals and cardiovascular events^12	Sweden	31	N/A	N/A	N/A
Gap between guidelines and reality in T2DM^13	Sweden	48	59	40	N/A
Quality of lipid-lowering study^14	Denmark	42	55	33	92% patients simvastatin 10 or 20 mg; 8% patients simvastatin 40 or 80 mg 80% patients pravastatin 20 mg; 20% patients pravastatin 40 mg 84% patients atorvastatin 10 or 20 mg; 16% patients atorvastatin 40 mg 75% patients lovastatin 20 mg; 25% patients lovastatin 40 mg 25% patients cerivastatin 200 µg; 75% patients cerivastatin 300 µg 72% patients fluvastatin 20 mg; 28% patients fluvastatin 40 mg
Oslo Heart Study^15	Norway	N/A	61% ♂ 40% ♀	N/A	N/A
Tromsø study^16	Norway	17%	25.7%	75%	N/A
Losartan Intervention For Endpoint reduction in hypertension (LIFE)^17	Iceland Norway Finland Sweden Denmark	N/A N/A N/A N/A N/A	31.6 40.8 32.3 34.7 30.9	N/A N/A N/A N/A N/A	N/A
Evaluation of Secondary Prevention Programme^18	Sweden	22	N/A	N/A	N/A
Goal achievement study in statin users^19	Finland	N/A	54.3 + CHD 35.8-CHD	N/A	60.2% of patients received simvastatin 10 mg; 81.2% atorvastatin 10 mg; 59.0% pravastatin 20 mg; 62.3% lovastatin 20 mg; 56.1% fluvastatin 20 mg
Goal achievement study in statin users^20	Finland	N/A	70.4 + CHD 54.3-CHD	N/A	48.0% of patients received simvastatin 10 mg; 68.0% atorvastatin 10 mg; 23.5% pravastatin 20 mg; 66.7% lovastatin 20 mg; 15.1% fluvastatin 20 mg
Study of statin use after acute MI^21	Norway	49%	54%	41%	N/A
Monitoring and treatment after MI study^22	Denmark	45.8	N/A	N/A	46% patients simvastatin 10 mg; 44% patients simvastatin 20 mg; 9% patients simvastatin 40 mg 64% patients pravastatin 20 mg; 36% patients pravastatin 40 mg
Goal achievement study^23	Norway	35.5	35.5	N/A	Average doses: simvastatin 22.7 mg; atorvastatin 16.8 mg; pravastatin 26.0 mg; lovastatin 32.0 mg; fluvastatin 31.6 mg; cerivastatin 0.2 mg
Secondary prevention study^24	Norway	7.8 (1994/95) 26 (1996/97)	N/A	N/A	N/A

CHD = coronay heart disease; N/A = not applicable.

Patients with coronary heart disease and diabetes

In patients with myocardial infarction (MI), the use of statins at discharge increased from 42 to 91% in patients with TC ≥5 mmol/L during the years 1995–1998, and in the same period goal achievement (TC <5.0 mmol/L) increased from 35 to 54% at post infarction control 8–12 weeks later 21. The Norwegian secondary prevention study in primary care found that patients with CHD and diabetes were treated like patients without diabetes 24. Findings from the Norwegian study in general practice seemed to be more encouraging. Goal attainment (TC <5.0 mmol/L and LDL-C <3.0 mmol/L) was greater in the diabetes subgroup (44.6%) than in the nondiabetes group (34.1%) or the total study population (35.5%). However, this may be caused by lower pretreatment concentrations of TC and LDL-C in patients with diabetes than in nondiabetics 23. In the Finnish goal achievement study among statin-treated patients, goal attainment was greater in patients with CHD (63%) than without CHD (37%) 9.

The Swedish National Diabetes Register includes data on approximately 80 000 Type 1 and Type 2 diabetic patients, showing that lipid lowering treatment rates as well as goal achievement have increased from 1996 to 2003, both in primary and specialist care. However, only 60% of the patients treated achieved a TC goal of <5.0 mmol/L in 2003, and if the newer guideline treatment goal of TC <4.5 mmol/L is applied; only 25% of women and 37% of men would achieve this 13. Likewise, in a Danish register study, more Type 2 diabetic patient received lipid lowering treatment and more achieved the goal in 2002 versus 2000. However, overall only 34% had a TC <5 mmol/L in 2002, whereas in the treated group the corresponding figure was 42%. A goal of TC <4.5 mmol/L would have been achieved in 25% 8.

Treatment patterns

Across all papers in this analysis, simvastatin, atorvastatin and pravastatin were the three most frequently used statins. Studies reporting on dosage showed that the majority of patients received statins at low or medium doses (Table II). Only a small proportion of patients received high-dose statin therapy as an initial regimen, and few patients initiated on lower doses were uptitrated. The average daily dose of simvastatin was 17.1 to 22.7 mg and of pravastatin 23.2 to 26.0 mg daily.

In general, younger patients were prescribed lipid-lowering agents more frequently than older patients (defined as ≥65, 70 or 75 years in the different studies) 15, 16, 24. Statin prescribing increased with baseline TC level, risk of CVD, and/or previously documented CVD 16. Overall, substantially fewer women than men were adequately treated during the observed years 7, 15–17, 24. Only between 22.6 and 40% of the women achieved the combined treatment goal of TC and LDL-C, in contrast to between 40 and 61% of men 15, 16, 18, 21, 23. The differences were attributable to different baseline levels of TC and LDL-C and not to higher doses of statin.

Discussion

Many of the studies included in this review have limitations, such as design of the studies, heterogeneous data collection and selection bias, which all might have impact on the review. However, the published literature demonstrates that in the Nordic countries there is a considerable need to raise the standard of lipid lowering therapy, a cornerstone in preventive cardiology. Although increasing numbers of patients with hyperlipidemia have been treated over recent years, treatment goals set by the Joint European Societies and in national guidelines are not being achieved in the majority of patients. Treatment goals are based on clinical trials, in which about half of the subjects remain above the target value. Therefore, in clinical practice all of the patients should obtain treatment goals.

There are a number of reasons for the unacceptably high numbers of patients not achieving their lipid treatment goals. The studies forming the basis of this paper demonstrate that physicians seem to be too cautious with initial dosages of statins and to have insufficient procedures for uptitration 23, 25. The daily simvastatin and pravastatin doses observed were lower than in the outcomes studies 4. There may be fear of side effects, as elevation of liver enzymes, myopathy, rhabdomyolysis, and cancer 26. It is commonly stated that the clinical experience from statins is so short that long term treatment may be hazardous, despite the 10 year data on persistent efficacy and safety from the 4S study 27. Furthermore, difficulties in extrapolating clinical trial data to their patients, and implementing the recommendations made in the guidelines are barriers that may prevent physicians from achieving best practice. Also, a close monitoring of the lipid profile with dose-adjustment is time-consuming and requires interest and extra effort of the physician 1–3. The deliberate non-compliance of some of the patients concerning lifestyle changes and medication also remains a limiting factor 28. Some data suggest that poor patient adherence might be the reason patients fail to meet their treatment goals in 46% of cases 29.

Both the Swedish and the Danish study in diabetic patients demonstrated low use of statins, and in the Danish study only half of the diabetics with an MI received statin treatment. This corresponds to the results from another Danish study where only 61% of post MI patients were treated with a statin 30. This is surprising as patients with diabetes are at high risk and benefit highly from statin treatment. Furthermore, patients with type 2 diabetes without CHD should be treated as aggressively with lipid-lowering therapies as patients with established CHD 1–3, 5.

The frequency of statin prescription was associated with baseline TC and increased risk of, or established CVD. Women were less likely to receive statin treatment than men and did not receive doses in accordance to their higher baseline cholesterol levels. This is consistent with previous findings of under-treatment in women with atherosclerotic disease 31. The guidelines for lipid-lowering treatment do not support treating the sexes differently 1–3, 5. In addition, a meta-analysis of large-scale clinical trials shows same benefit of statin therapy in men and women 4. In our analysis, younger patients were prescribed lipid-lowering agents more frequently than older patients. This is in line with recent reports 32. However, also older patients seem to benefit from statin therapy at least as good as younger patients 4, 33, 34.

How can CVD prevention be improved? Educating prescribing physicians is an important issue. In Denmark, post-graduate training combined with medical audit has recently been shown to raise the quality of cardiovascular care in general practice 35. Over the course of the intervention period, TC and LDL-C levels decreased from 5.5 to 4.8 mmol/L and 3.3 to 2.8 mmol/L, respectively. The statin doses were higher, and more patients were treated. Studies have also shown that health screening can decrease cardiovascular risk in the general population, irrespective of the use of medication. A five-year randomized, controlled trial in Ebeltoft, Denmark, demonstrated that health screenings reduced cardiovascular risk score, body mass index and TC levels, with most benefit seen in high risk individuals 36.

There is now considerable evidence that aggressive lowering of LDL-C reduces cardiovascular events, whereas more moderate interventions allow for continued progression (the lower the better principle) 4, 37, 38. Consequently, national and international guidelines are setting progressively lower targets for LDL-C, particularly in high risk patients. In secondary prevention for patients at very high risk (e.g. individuals with multiple major risk factors for CHD, diabetes plus CHD, severe and poorly controlled risk factors, multiple risk factors for metabolic syndrome, and patients with acute coronary syndrome (ACS)) an LDL-C below 1.8–2.0 mmol/L is now recommended 3, 5, 38. Finland, Norway and Sweden have already adjusted the treatment guidelines to include more aggressive goals (TC <4.5 mmol/L, LDL-C <2.5 mmol/L in patients at very high risk). In Denmark, the Danish Cardiology Society recommends <4.5 mmol/L and <3.0 mmol/L for TC and LDL-C, respectively, in high-risk patients.

Clearly, with these new, challenging targets, fewer patients will be able to achieve their treatment goals non-pharmacological, and an increasing number of patients will become eligible for drug treatment for the first time. For many patients, the efficacy offered by traditional statin monotherapy will be suboptimal even with the use of potent statins 37, 39 and high statin doses. Upward dose titration can provide some improvement but doubling the initial dose of a statin typically results in only a 6% additional reduction in LDL-C 2. The use of dual therapies with complementary modes of action is often standard in other therapeutic areas such as hypertension and diabetes. By combining a statin and the cholesterol absorption inhibitor ezetimibe, more patients achieve their treatment goals at lower doses of statin and with tolerability similar to that of statin monotherapy 40. Combination therapy with nicotinic acid and fibrates necessitates additional tolerability and safety considerations 2.

Lifestyle changes combined with appropriate use of medications can dramatically reduce the risk of CHD, stroke, and death from heart disease. Patients should know their cholesterol numbers, to enable them to see how much lowering is needed to reach target levels. However, even with intensive drug therapy and an appropriate diet and exercise program, many patients still will have recurrent cardiovascular events. New strategies may include the development of new agents to achieve even lower LDL-C target levels, substantially increase HDL levels, reduce triglycerides and components of inflammation, and modify other identified components of vascular disease 41.

In conclusion, in the Nordic region there is an increasing use of lipid-lowering agents, but more than 50% of patients receiving lipid-lowering drugs are still inadequately treated. National and international guidelines committees are recommending progressively lower TC and LDL-C levels, and meeting these revised targets is becoming constantly more challenging. Despite higher doses of potent statins, standard statin monotherapy is often no longer sufficient to achieve treatment goals, and combination therapy to inhibit both cholesterol absorption and cholesterol production may often be needed, together with reinforced and intensified therapeutic lifestyle modifications. Physicians and patients should also invest time in educational initiatives aimed at improving their understanding of cardiovascular disease and its treatment options.

Conflict of interest statement: This study was supported by Merck & Co and Schering Plough, but data analyses and conclusions drawn were made by the investigators. Of the investigators AS, TS, ME, and AW have had scientific, educational and consultation cooperation with various companies (including Merck & Co and Schering-Plough) marketing lipid-lowering products. PH has received consulting and speaking fees from AstraZeneca, Bristol-Myers Squibb, Merck & Co and Pfizer.