Impact of New Joint British Societies’ (JBS 2) Guidelines on Prevention of Cardiovascular Disease: Evaluation of Serum Total Cholesterol Goal Achievement in UK Clinical Practice*

By Rajagopalan, Srinivasan Alemao, Evo; Finch, Liz; Yin, Don

Key words: Coronary disease – Hydroxymethylglutaryl CoA reductase inhibitors – Hypercholesterolemia – Prevention and control – Treatment outcome ABSTRACT

Background: Consensus health panels, including the Joint British Societies (JBS), have established increasingly stringent cholesterol goals. However, in clinical settings, most patients do not achieve even the less stringent goals.

Objective: To provide descriptive data on the proportion of patients in the United Kingdom who would have achieved the new JBS 2 total cholesterol (TC) goal of < 4.0 mmol/L (< 155 mg/dL) without changes in therapy.

Methods: Cross-sectional analysis of patients initiated on lipid- modifying therapies in 2005 (before publication of the JBS 2 guidelines), as ascertained via a physician (general practitioner (GP)) database.

Results: Among 70 194 patients (mean age 64 years) receiving prescriptions for lipid-modifying therapies, 35823 (51 .0%) were considered to be at high risk because of CHD or diabetes mellitus and 34371 (49.0%) were at low risk. A total of 66 642 (94.9%) patients received monotherapy with HMG-CoA reductase inhibitors (statins), including 33853 (94.5%) of high-risk patients and 32789 (95.4%) low-risk individuals. Statins were prescribed at medium (maximum daily dose = simvastatin 40 mg; atorvastatin 20 mg; rosuvastatin 10 mg) or lower equipotency doses in the majority of patients receiving these medications – 58 033 (87.1%) patients receiving statins, including 28988 (85.6%) high-risk patients and 29045 (88.6%) low-risk patients. Of the 28874 patients with TC measurements, 7827 (27.1%) would have achieved the new JBS 2 goal without changes in medications or doses. In more than 51 % of patients, TC values were >/= 10% above the JBS 2 target despite prescribed therapy, suggesting that these individuals would also not have achieved the JBS 2 goal by doubling their statin doses.

Conclusions: Even though patient data were accessed before the JBS 2 guidelines were issued and data on other cardiovascular risk factors not captured, it can be concluded that most British patients (approximately 73%) would not have achieved the recent JBS 2 TC target of < 4.0 mmol/L without changes in lipid-modifying medications or medication doses. More effective and well-tolerated treatments, including combination statin regimens, are needed to increase the proportion of British patients reaching the more stringent JBS 2 goal.

Introduction

Cardiovascular disease is a leading cause of mortality and morbidity in industrialized societies. In the United Kingdom (UK), coronary heart disease (CHD) kills > 1 10000 people annually, and it also results in 275 000 cases of myocardial infarction (MI) and more than 1 .4 million cases of angina pectoris’. In the Health Survey for England (2003), 26-34% of men and 14-25% of women ages >/= 65 years reported a history of CHD or stroke2.

The initial guidelines of the Joint British Societies (JBS 1) embraced the concept of absolute (total) coronary risk and advocated the use of gender-specific coronary risk prediction charts in guiding treatment decisions3. However, CHD ‘was given top priority in these guidelines’4. The JBS 1 guidelines advocated comprehensive risk factor assessment and management (including lipid-modifying pharmacotherapy) of all patients with a 10-year absolute CHD risk >/ =30%3.

However, in a staged public-health approach, the JBS 1 guidelines recommended that individuals with 10-year absolute CHD risk = 15- 29% receive comprehensive risk factor management and treatment only after patients with 10-year absolute CHD risk S 30% had been effectively targeted and ‘as (public healthcare) resources allow’3. According to the JBS 1 guidelines, drug therapy was not recommended for individuals with 10-year absolute CHD risk <15% unless severe hypertension, target organ damage, inherited dyslipidemia, or diabetes mellitus with associated target organ damage was present3. In patients with established CHD and in certain patients with other manifestations of atherosclerosis, JBS 1 specified treatment targets of total cholesterol (TC) less than 5.0 mmol/L (< 195 mg/dL) and low- density lipoprotein cholesterol (LDL-C) less than 3.0 mmol/L (< 117 mg/dL).

As early as 2000, however, randomized controlled trials had demonstrated clinical benefits of lipidmodifying therapy in patients at 10-year absolute CHD risk thresholds as low as 6% (or approximately 8% for 10-year absolute cardiovascular risk). The JBS 1 and National Service Framework policy for lipid prescribing was viewed as excessively conservative by the National Institute for Health and Clinical Excellence (NICE), which recommended statins for adults with clinically evident cardiovascular disease and for primary prevention of cardiovascular disease in adults with 10-year absolute cardiovascular risk >/=20%4.

Consistent with the stance of NICE, the JBS 2 guidelines recognized that ‘any symptomatic manifestation of atherosclerosis in any vascular territory puts a person at high risk of dying from cardiovascular disease, mainly from (CHD)’ and did not distinguish between primary and secondary coronary prevention4. Under the new guidelines, clinical practice should ‘focus equally on people with established atherosclerotic (cardiovascular) disease, people with diabetes, and asymptomatic individuals at high total risk’ (10year absolute cardiovascular risk >/=20%)4. All these individuals would be considered high risk and would be treated to the same lifestyle objectives and targets for lipids, blood pressure, and glucose4. The new, more stringent JBS 2 targets for high-risk patients included a TC < 4.0 mmol/L (< 155 mg/dL) and a lowdensity lipoprotein cholesterol (LDL-C) < 2.0 mmol/L (< 78 mg/dL)4.

The purpose of the present study was to provide descriptive data concerning the proportion of British outpatients seen by general practitioners (GPs) at a single time point before publication of the JBS 2 goals who would have attained these more stringent TC targets without changes in lipid-modifying medications or doses.

Methods

Study setting and design

In this cross-sectional study, a proprietary GP physician database (MediPlus; IMS Health; London, UK; available at URL: http:/ /research.imshealth.com/databases/ databases. htm#mediplus) comprising approximately 730 GPs was analyzed. The UK Medicines Control Agency uses the database for pharmacovigilance purposes. Analyses of the database by IMS Health have demonstrated that the panel of GPs is broadly representative of the overall UK population and that patient gender and ages are also consistent with national statistics for the UK.

The computerized database linked patient records from different health settings, enabling analyses of healthcare pathways, treatment efficacy, and treatment costs. Laboratory test results (e.g., serum cholesterol), treatments, referrals, and outcomes (e.g., hospitalization) can be linked to diagnoses by ICD-10 (and other) criteria. Patient age, gender, and certain comorbidities (e.g., diabetes mellitus) were available in anonymized form.

Ethics

This was a non-interventional (observational) data review, and no investigator had access to non-anonymized data. To ensure confidentiality, MediPlus extracts only selected information in accordance with guidelines from the Royal College of General Practitioners (available from URL http://www.rcgp.org.ul) and the British Medical Association (available from URL http:// www.bma.org.uk). No patient-identifiable data were collected, and each patient was assigned a system code unique to each GP office’s computer. Although physicians could review all clinical information before transmitting it to the MediPlus database’s private secure network, all data were encrypted before transmission. The GPs in the IMS Health database were members of the UK National Health Service (NHS), whose Research Ethics Committee must approve research involving data collected from the NHS. This requirement was fulfilled through a submission to the Research Ethics Committee via IMS Health.

Data extraction and analysis

Records of patients receiving a prescription for a lipidmodifying therapy between January 1 and October 3 1 , 2005 (approximately 1 month before publication of the JBS 2 guidelines) were eligible for analysis. Only patients who had a prescription for a lipidmodifying therapy and a TC measurement > 30 days after receiving the prescription were eligible for analysis.

Statins were classified using the Maron formulation for comparative cholesterol-lowering capacity5. Under this system, daily doses of atorvastatin <20mg, simvastatin

Table 1. Patient characteristics

Results

Patient characteristics A total of 70 194 patients (mean age 64.1 years +- 10.0 years) who received prescriptions for lipid-modifying therapies were included (Table 1). Of these, 35 823 (51.0%) had CHD or diabetes mellitus and were considered to be at high risk, while the remaining 34371 (49.0%) were at low risk. Most patients (58.0%) were men. The mean serum TC concentration was 4.6 +- 1.1 mmol/L (179 +- 42 mg/dL).

Lipid-modifying treatment

Among 70194 patients receiving prescriptions for lipid-modifying therapies, 66 642 (94.9%) received statin monotherapy, followed by >/ = 2 lipid-modifying therapies in 3.9% and other forms of monotherapy, such as ezetimibe, niacin, fibrates, or bile acid resins, in 1.1% (percents do not sum to 1 00 because of rounding) . A total of 33 853 (94.5%) high-risk patients and 32 789 (95.4%) low- risk individuals received statins. Statins were prescribed at medium (maximum daily dose: simvastatin 40 mg; atorvastatin 20 mg; rosuvastatin lOmg) or lower equipotency doses in 58033 (87.1%) patients receiving statins, including 28 988 (85.6%) high-risk patients and 29045 (88.6%) low-risk patients (Table 2).

JBS 2 goal attainment

A total of 7827 (27.1 %) of 28 874 patients with available data on serum TC measurements would have achieved the JBS 2 goal of TC < 4.0 mmol/L (< 155 mg/dL) without changes in medications or doses (Table 3). Among 16348 patients with CHD or diabetes mellitus, 5660 (34.6%) would have attained the JBS 2 TC goal without treatment changes. In all, 14928 (51.7%) of 28 874 patients were S: 10% above the JBS 2 target for TC.

Table 2. Lipid-modifying therapies prescribed

Discussion

The majority of patients (approximately 73%) treated by British GPs before publication of the JBS 2 guidelines would not have achieved the new, more stringent TC target of <4.0mmol/L (<155mg/ dL) without changes in medications or medication doses. Most patients (approximately 95%) received prescriptions for statin monotherapy and most (approximately 87%) received prescriptions for statins of medium or lower equipotency. Very few (< 5%) patients received combination regimens or therapies other dian statins.

Most patients (approximately 52%) were Pounds 10% above the JBS2 TC target even though findings from many clinical studies have clearly demonstrated that sustained reductions in TC and LDL-C (and cholesterol goal achievement) are associated with significantly improved treatment outcomes in patients at elevated cardiovascular risk. The present results suggest that these patients would not have achieved the TC target even if their statin doses had been doubled. Because of flattening of the dose-response curve for statin-induced cholesterol lowering, each doubling of statin doses lowers TC marginally: by 5% on average6. In addition, many patients (up to 10%) cannot tolerate high-dose statin regimens. Clinical trials have demonstrated significant increases in frequencies of adverse events (e.g., myopathy, elevations in serum transaminases) with high-dose statins, and such intensive therapies may require more intensive monitoring7-11. It has been argued that each doubling of statin doses also doubles the frequency of elevated liver enzymes (>3 times upper limit of normal)6.

Table 3. Total cholesterol (TC) goal attainment for patients on lipid-modifying therapy, according to history of coronary heart disease or diabetes mellitus (high-risk) according to Joint British Guidelines issued in 1998 (JBS)3 and 2005 (JBS 2)4

A number of management strategies have been proposed to potentiate the TC- and LDL-C-lowering capacities of lipid-modifying therapies and increase proportions of patients achieving consensus cholesterol targets. One approach is to administer combination therapies, including the cholesterol absorption inhibitor ezetimibe with statins12-22 or niacin with statins23. Such therapies directed toward two or more pharmacologic mechanisms may assist in achieving treatment goals without increasing the frequency or severity of adverse events associated with higher-dose monotherapy. However, when administered alone or with statins, niacin has been associated with certain tolerability problems, including adverse cutaneous effects (e.g., flushing)24,25.

Another approach in patients with inadequate responses to lipid therapies is to change to another form of therapy. Studies have demonstrated that treatment with the higher-potency statin rosuvastatin is associated with enhanced cholesterol goal attainment compared with other forms of statin monotherapy26-29. Upward adjustments and changes in lipid therapies are relatively infrequent in clinical practice30,31. In theory, switching some patients’ statin monotherapy to rosuvastatin might have improved cholesterol goal attainment. On the other hand, a recent study suggested that patients who change from one statin treatment to another are significantly less likely to adhere to the new medication regimen compared with patients remaining on their initial statin (p < 0.00 1)32.

Recent studies have demonstrated that the use of clinical algorithms to individualize starting doses of statin monotherapy according to baseline and target cholesterol values (and overall baseline cardiovascular risk) can also increase the proportion of patients achieving cholesterol goals33,34. However, in the present analysis, most patients received prescriptions for statins at medium or lower equipotency doses.

One potential risk factor for suboptimal cholesterol goal achievement and the occurrence of CHD that is often overlooked by clinicians is poor adherence with lipid-modifying medication prescriptions and therapeutic lifestyle counseling. Adherence to lipidmodifying medication regimens may be lower in naturalistic primary-care settings (e.g., GP offices35) compared with randomized controlled trials36. A number of patient factors may undermine adherence to lipid-modifying therapies, including lack of knowledge about hypercholesterolemia, cardiovascular risk, and cholesterol targets; insufficient perception of the threat to health posed by cardiovascular disease37; and negative beliefs concerning the efficacy and tolerability of medications to lower cardiovascular risk31,38-41.

Other possible impediments to medication adherence include medication costs, inadequate access to physicians, and poor patient- physician communication or rapport42,43. Complicating the issue, many physicians choose not to follow consensus guidelines44,45, partly because of deficient knowledge of, or negative attitudes toward, these guidelines38,46. As obstacles to implementation of consensus guidelines and other forms of coronary prevention (e.g., initiating statin treatment), GPs cite concerns about medication costs, patients’ ability to understand and adhere to treatment recommendations, increased workload and insufficient time of healthcare providers, and difficulty in risk-stratifying patients to target treatment47,48. A recent pharmacy intervention, including 6 months of pharmacist follow-up, patient education, and use of time- specific packs for medication dispensing, significantly improved both medication adherence and the observed decreases in LDL-C and blood pressure compared with an intervention-free run-in (p < 0.00 1)38,49.

Limitations of this study include the fact that attainment of the new JBS 2 target for TC was assessed before the JBS 2 guidelines had been issued. This timing may have resulted in underestimating cholesterol goal attainment, given the publicity and educational programs for patients and physicians that are often provided upon the release of new consensus guidelines. In addition, NICE is developing a new strategy for the assessment and treatment of cardiovascular disease (e.g., lipid modification), which is scheduled to be published in December 2007(50). Incorporation of emerging guidelines into General Medical Services contracts might introduce further incentives for British GPs to identify, counsel, and treat patients at increased cardiovascular risk to their consensus cholesterol targets.

Among patients with CHD or diabetes mellitus in the present study, only 34.6% had TC values below 4.0 mmol/L. This proportion may overestimate actual goal achievement because the JBS 2 states that ‘the optimal total cholesterol target is < 4.0 mmol/L and lowdensity lipoprotein (LDL) cholesterol < 2.0 mmol/L, or a 25% reduction in total cholesterol and a 30% reduction in LDL-C, whichever gets the person to the lowest absolute value (italics by JBS 2)'4. Because data on LDL-C were frequently missing in this study, achievement of the new LDL-C target could not be determined. Given the cross-sectional nature of the study, percent decreases from baseline in TC or LDL-C with treatment could also not be evaluated. Finally, other cardiovascular risk factors, including smoking, diet, physical inactivity, obesity, or abdominal adiposity were not captured. A study of clinical decision making using hypothetical case vignettes suggested that different GPs use such lifestyle-related risk factors as justification for or against initiating lipid-modifying pharmacotherapy51. This study also suggested that presentation of angina pectoris more frequently triggered decisions to initiate lipid treatments than did die presence of diabetes mellitus, possibly because diabetes has become recognized as a 'CHD risk equivalent' more recendy52.

Data on lipid-modifying therapy prescriptions are also surrogate measures of actual medication-taking behaviors. Given diat a number of patients in general practice would be expected not to fill their prescriptions or to use medications inconsistently over time, the finding diat 27% of patients would have achieved die new JBS 2 TC goal without treatment changes might overestimate the overall proportion of UK residents with increased cardiovascular risk who achieve this goal.

The external validity of these findings might also be open to challenge based on the higher mean TC and blood pressure values, as well as the significantly higher proportion of patients with a history of stroke, in the low-risk group compared with the high- risk group. In addition, some studies have suggested that relatively low proportions of GPs and other primarycare physicians adhere to consensus guidelines, and low proportions of patients in primary- care practices achieve cholesterol targets35. Only the records of patients with valid TC measurements approximately 30 or more days after receiving their lipid treatment prescription were eligible for analysis. A previous study showed that frequent physician follow- up, particularly lipid and lipoprotein measurements soon after the initiation of lipid-modifying therapy, is associated with enhanced medication adherence53. The possible selection bias toward a more adherent patient population in this study, which excluded patients without TC measurements, might have resulted in overestimating cholesterol goal attainment compared with a wider patient sample followed over time. Conclusions

The majority (approximately 73%) of UK patients treated by GPs before publication of the JBS 2 guidelines would not have achieved the newer, more stringent goal of TC <4.0mmol/L (<155mg/dL) without changes in lipid medications or doses. More than 51% of patients required >/=10% reductions in TC to achieve the JBS 2 goal, suggesting that they would not have achieved these goals even if their statin doses had been doubled. More effective and well- tolerated therapies, including combination statin regimens directed toward two or more pharmacologic mechanisms, as well as efforts to enhance adherence to medications and therapeutic lifestyle counseling, are needed to increase the proportion of UK patients achieving JBS 2 cholesterol targets.

Acknowledgments

Declaration of interest: This study was funded by MSP (Merck/ Schering-Plough) Singapore Co. LLC. All authors contributed to the study concept and design and the acquisition of data. All authors drafted the manuscript. Critical revision of the manuscript for important intellectual content was done by all authors. LF, SR, and EA performed die analysis and interpretation of data. Statistical analysis was done by SR. EA provided administrative, technical, and material support.

EA, LF, and DY are employees of (and shareholders in) Merck & Co., Inc. SR is a paid consultant to Merck. Assistance in manuscript preparation was provided by Stephen W. Gutkin, Rete Biomedical Communications Corp., Ridgewood, NJ, USA.

* Portions of this study were presented at the World Congress of Cardiology, September 2-6, 2006, Barcelona, Spain

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3926_6, Accepted for publication: 19 June 2007

Published Online: 19 July 2007

doi:10.1185/030079907X219472

Srinivasan Rajagopalan a, Evo Alemao b, Liz Finch c and Don Yin b

a Med Data Analytics Inc., Williamsville, NY, USA

b Merck & Co., Inc., Whitehouse Station, NJ, USA

c Merck Sharp & Dohme Ltd, Hoddesdon, UK

Address for correspondence: Srinivasan Rajagopalan, PhD, Med Data Analytics Inc., 5500 Main Street, Suite 313, Williamsville, NY 14221, USA. Tel.: +1 716 807 6604; Fax: +1 716 692 2661; sr62@columbia.edu

Copyright Librapharm Aug 2007

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