Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

4th Canadian Therapeutics Congress

Halifax, Nova Scotia / May 27-30, 2007

With newer trials indicating that outcomes are usually better the lower the LDL-C levels are, the new LDL-C targets are increasingly difficult to achieve, especially in high-risk patients, for whom an LDL-C of less than 2.0 mmol/L is now deemed reasonable. Complicating the increasing challenge of driving LDL-C down to unprecedented levels is the growing recognition that only a minority of patients have elevated lipids as a single cardiovascular disease (CVD) risk factor—thus, most patients with dyslipidemia are at moderate to high risk for CVD events. Indeed, in a cross-sectional study carried out in four Canadian regions, investigators found that 31% of 1103 patients with dyslipidemia had one additional CVD risk factor, 28% had two additional risk factors and 19% had three additional risk factors.

The Assessing Cardiovascular Targets (ACT) program including over 17,000 CVD patients from 450 general practices across the country also found that patients, on average, had two CVD risk factors, while over 40% of the cohort had three or more risk factors. Achieving target LDL levels in real-life practice settings despite almost universal statin therapy is also not optimal, especially among high-risk patients.

Regarding the cross-sectional Canadian cohort, Dr. Mitchell Levine, Professor of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, and colleagues found that overall, physicians did very well at getting their low-risk patients to LDL goals of 4.5 mmol/L with 96% of this group achieving LDL targets. Some 79% of moderate-risk patients also achieved LDL-C goals of 3.5 mmol/L, but for the high-risk patients for whom targets for this study were 2.5 mmol/L, only 62% reached this goal.

Interestingly, about one-third of patients in this Canadian cohort met the criteria for the metabolic syndrome but mean changes in LDL-C of about 1.7 mmol/L between pre- and post-treatment levels were no different in patients with the metabolic syndrome than they were for patients without it.

“Patients reported attempts at dietary change,” added Dr. Levine, “but we are not seeing any differences in LDL reduction [attributable to diet].”

Extrapolating these findings to the CVD risk population, the McMaster University group calculated that of the 3.1 million Canadians using lipid-lowering therapies in 2004, 1.6 million would be high-risk, 1.1 million would be at moderate risk and 0.4 million at low risk for CVD events. Thus, by preventing a proportion of non-fatal myocardial infarctions based on clinical trial calculations, statin therapy has the potential to save the health care system some $61 million a year among high-risk patients, $21 million a year for moderate-risk patients and $2.4 million a year for those in the lowest risk category.

Prevention of ischemic stroke with statin therapy in turn has the potential to save the health care system $238 million a year, and these figures do not take into account the value of health benefits derived from CVD event prevention, Dr. Levine noted.

Interpatient Genetic Variability and Pharmacokinetics

If a gap remains between LDL levels recommended by expert panels and those achieved in the community, early research into interpatient genetic variability may explain why some patients are either more or less sensitive to the effects of the statins. As discussed by Rommel Tirona, PhD, Assistant Professor, Department of Physiology and Pharmacology, University of Western Ontario, London, there is wide interpatient variability in statin effects and blood levels.

He and colleagues have been studying the hepatic statin transporter OATP1B1, which is known to act on rosuvastatin, among other agents of this class.

Clinical trials carried out in Asia showed that Asians had twofold higher levels of rosuvastatin than Caucasians at the same dose. It would appear that at least some Asians carry a polymorphism in the OATP1B1 statin transporter and that this defect may well explain why they develop higher blood levels when treated with rosuvastatin and why it is recommended that rosuvastatin be initiated at a dose of 5 mg in this patient population.

An exploration of genetic determinants of pravastatin efficacy also showed that a rare polymorphism in HMG Co-A reductase affected the efficacy of the statin, Dr. Tirona told listeners. Another transporter, the breast cancer resistance protein, also appears to have an effect on statin disposition, “not at the level of the liver, but at the intestinal barrier, where it is expressed and impedes absorption of statins from the gastrointestinal tract,” he explained. Defects in this particular protein therefore are also important to statin disposition.

“The genetics of and drug interactions involved in these hepatic drug transporters are important determinants of variability in statin disposition,” Dr. Tirona confirmed. However, he added that it would be premature to draw any firm conclusions and as such, many unknown determinants behind the variability of statin effects are yet to be elucidated.

Differences exist between statins with respect to drug interactions which commonly occur in patients undergoing multiple treatment regimens. All drug interactions have a pharmacokinetic or pharmacologic basis and are predictable, given an understanding of the pharmacology of the drug involved. The most clinically relevant of the statin interactions involves alterations of the metabolic pathways within the cytochrome P450 (CYP) system. CYP 3A4 metabolizes atorvastatin, lovastatin and simvastatin, while rosuvastatin avoids metabolism by CYP 3A4. When other compounds are similarly metabolized through the same enzymatic pathway—as are up to 70% of agents—there is considerable potential for drug-drug interaction. For example, when a statin such as simvastatin is given in the presence of a macrolide, the combination can cause up to 20-fold increases in statin levels. Knowledge of the pharmacokinetic properties of the statins can help avoid the majority of drug interactions.

Improving Outcomes

If genetic determinants of statin response are not yet fully understood, it is very clear that there are major differences in the potency of the statins and these differences have important implications for patients and payers alike.

For example, results of a meta-analysis showed that rosuvastatin 5 mg had the same LDL-lowering effect as simvastatin 40 mg, while rosuvastatin 10 mg produced effects equivalent to those of simvastatin 80 mg. No dose of simvastatin appeared equivalent to rosuvastatin at either 20 mg or 40 mg. In real numbers, changes in LDL-C from baseline based on STELLAR (Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin) data were virtually identical for the two drugs at approximately 46% for rosuvastatin 10 mg and simvastatin 80 mg.

According to investigators, these differences in the magnitude of LDL-C reduction are important because payers should be taking into account what it costs to achieve a certain magnitude of LDL-C reduction and not what an individual tablet costs.

As observed in terms of a per cent reduction in LDL-C levels, a cost comparison presented by consultant Gordon Polk, Drug Benefit Consulting, Burlington, Ontario, showed that it costs between $496 and $726 a year to treat patients with 10 mg to 40 mg rosuvastatin, or a weighted average of $11.10 for each 1% reduction in LDL-C.

He reported that this is actually significantly less than it costs to achieve the same 1% reduction in LDL-C for either atorvastatin 10 mg or 80 mg, at a weighted average cost of $17.04. Similarly, costs for generic pravastatin 10 to 40 mg to achieve the same 1% reduction in LDL-C are $16.76 and $15.44 for 10 to 80 mg of generic simvastatin.

These findings also suggest that at a dose of 10 mg, over 82% of patients treated with rosuvastatin achieve LDL-C target levels vs. approximately 69% of patients on atorvastatin 10 mg, 31% of patients on pravastatin 10 mg and 51% of patients on simvastatin 10 mg. In Polk’s opinion, “Generally speaking, most payers just look at the cost of the drug rather than look at what the drugs achieve in terms of their therapeutic outcomes.” He added, “What we found here is that rosuvastatin has a better therapeutic outcome and is more cost-effective than other statins, so as a payer, you may be paying for a drug that doesn’t achieve the desired results.”

Patient Preferences

Guidelines suggest that if the initial dose of a statin proves suboptimal, it should be increased to achieve target LDL-C levels.

However, in a study assessing what patients would prefer, investigators found that patients would prefer to have their prescription changed if they are not at target rather than have the dose increased, and that only a small proportion of patients prefer to have a second drug added to achieve their lipid goals.

For this study, a questionnaire was mailed to over 100,000 households of patients who had identified themselves as using a lipid-lowering drug and approximately 44,000 of them returned the questionnaire.

Three-quarters of respondents reported being on a lipid-lowering drug for two or more years and the majority of them were on atorvastatin. Asked how they felt about medication change in general in order to achieve their LDL-C goals, 52% indicated they preferred physicians to change their current therapy to another drug, compared with 43% who said they preferred to have the dose of their current drug increased. According to these findings, only 4% would prefer their physician to add a second drug.

Investigators collaborating on the questionnaire indicated that patients typically prefer to use the lowest dose possible of a medication, and that if a change is still needed for them to attain optimal health, they choose to have their treating physician try a completely different strategy rather than add to their existing regimen. Investigators conceded that this would not necessarily adhere to guideline recommendations, but that if physicians decide to increase the medication dose, this might affect patient compliance.

In the end, compliance is the only way patients are going to realize the benefits of statin therapy and any effort that enhances compliance should be encouraged, investigators reported.

Encouraging Compliance

One successful model that is producing encouraging compliance rates is the Healthy Changes support program, a triple-pronged, patient-focused scheme designed to help patients remain on statin therapy and derive the benefits from LDL-C lowering.

All patients registered with the program received telephone coaching from a registered dietitian. They also received an information kit detailing how they could modify their lifestyle with an emphasis on healthy eating and regular physical exercise. Perhaps most importantly, they were also educated on the importance of getting their cholesterol under control and why they would need to remain compliant.

At the end of six months, 95% of patients enrolled in the support program were still taking rosuvastatin as prescribed, and 91% were still adherent at the end of 12 months.

Program collaborators reported that this was in contrast to typical compliance rates, where only about 70% to 75% of patients are still on a statin at the end of one year. They told delegates that the program puts the patient in the centre and sets up a good model for change. Consequently, there is a potential benefit for patients who adhere to their regimen as well as for the health care system in terms of fewer cases of myocardial infarction and stroke.

The Global Cardiovascular Picture

As important as it is for patients to achieve their LDL-C targets, elevated lipids are only one factor among the many risk factors that contribute to CVD.

As emphasized by Dr. Pendar Farahani, Clinical Lecturer in Family Medicine, McMaster University, it is essential for physicians to target their patients’ global CVD risk burden, not just elevated lipids, in order for their patients to achieve optimal CVD risk reduction. To that end, there appears to be a significant gap between what would constitute successful global CVD risk reduction and what is currently achieved.

As discussed by Dr. Levine, based on ACT cross-sectional data involving 1103 Canadian patients with dyslipidemia, over half (52%) were deemed to be at high risk, 34% were at moderate risk and 14% were at low risk. When investigators assessed whether patients had achieved not just LDL target goals, but targets for systolic and diastolic blood pressure as well as for fasting blood glucose levels, only 21% of high-risk patients were successfully at goal for all CVD risk factors, as were 50% of moderate-risk patients and 73% of low-risk patients.

“Despite success in reducing LDL-C, there are still considerable CVD risks that are inadequately managed to obtain global CVD protection in patients at moderate to high risk for CVD events,” investigators concluded.

Summary

To achieve the best possible outcomes for patients at risk for CVD events, risk factors including LDL-C need to be optimally managed. This is clearly challenging, as target levels for CVD risk factors are further lowered, making achievement of these goals increasingly difficult. Physicians therefore need to assess patients on an individual basis for optimal CVD risk management based on factors such as response to LDL therapy and to maximize therapeutic outcomes with the minimum amount of risk.