Clinical Implications of Switching Lipid Lowering Treatment from Rosuvastatin to Other Agents in Primary Care

Large-scale observational studies have shown that there is a continuous positive correlation between low-density lipoprotein cholesterol (LDL-C) concentrations and the incidence of clinical manifestations of atherosclerotic cardiovascular disease [1].

Back in 2005, the Cholesterol Treatment Trialists’ Collaboration reported a meta-analysis of 14 randomized trials of statin therapy versus control [2]. The results of this analysis showed that lowering of LDL-C by about 1 mmol/L (38 mg/dL) with a standard statin treatment safely reduced the 5-year incidence of major coronary events, revascularizations, and ischaemic strokes by about a fifth [2]. An updated meta-analysis of 26 clinical trials from the same research group, published 5 years later showed that additional reductions in LDL-C achieved with more intensive statin therapy, could further reduce the incidence of major atherosclerotic cardiovascular events [3].

As a matter of fact, statins significantly differ in their potency (LDL-C lowering effect/mg), with rosuvastatin being the most effective agent of this pharmacological class in reducing LDL-C [4]. The usual clinical dosage of 10-40 mg/day of rosuvastatin has been shown to achieve a 46-55% reduction in LDL-C [5].

Recently, the introduction of generic statins has enabled highly cost-effective LDL-C reduction in clinical practice and third party payers often recommend substitution of branded agents with generic alternatives [6]. However, even if switching from brand-name drugs to generic equivalents may reduce prescription costs, it may also potentially compromise therapeutic benefits if generic options are not of equivalent efficacy [7]. In fact, switching from a particular statin to another non-equipotent lipid lowering treatment may alter lipid control by causing a significant LDL-C increase [7, 8]. In line with this observation, switching from more effective to less effective lipid lowering agents has been associated with a higher probability of negative clinical outcomes in high risk clinical conditions [8, 9].

The aim of this study was to assess the clinical impact of switching from rosuvastatin treatment to any other lipid lowering therapy on clinical outcomes in the Italian general practice setting.

The analysis in this article was based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

The final study population included 10,368 new patients that started on “high-intensity statin treatment” [19] with rosuvastatin (10–40 mg/day) in the period between January 2011 and December 2013 according to the inclusion criteria.

During the entire period of observation, 2452 (23.6%) patients were switched from rosuvastatin to another lipid lowering treatment. Most of the patients were switched to atorvastatin (55.6%), followed by simvastatin (24.9%), simvastatin/ezetimibe (10.0%) combination and other statins (9.5%). Besides, in the vast majority of cases this therapeutic substitution could be considered as non-equipotent in terms of LDL-C reduction and according to current definitions [19], most patients (1777; 72.4%) were switched to “medium” or “low intensity” statin treatment (10–20 mg/day of atorvastatin in 1042 patients; 42.5%; 10–20 mg/day of simvastatin in 502 patients; 20.4%; other low-potency statin agents, such as pravastatin and lovastatin in 233 patients; 9.5%).

Demographic and clinical characteristics of the study population at baseline are reported in Table 1 showing significantly higher percentages in switched patients for most of the analyzed variables; in particular, more patients in the switch group had a history of hypertension or CKD, were taking ACE inhibitors, diuretics or antiplatelet drugs (p value <0.0001).

According to multivariate analysis with Cox proportional hazards method, factors independently associated with a higher probability of switch during the observation period were female gender (HR = 1.10, 95% CI: 1.02–1.19) and the presence of chronic kidney disease (HR = 1.47, 95% CI: 1.16–1.86).

As to the primary end point, during the observation period, 113 patients experienced an AMI, with an overall incidence of 6.7 AMI/1000 patient-years.

The incidence of AMI in patients remaining on rosuvastatin was 6.3 AMI/1000 patients-years (87 events), while it was 8.3 AMI/1000 patient-years (27 events) in patients switched to other lipid lowering therapies.

Multivariate analysis with Cox proportional hazards method, including switching as a time-dependent covariate demonstrated that after adjustment for all available demographic and clinical variables, treated hypertension (HR 0.6, 95% CI 0.4–0.9, p = 0.02), female gender (HR 0.5, 95% CI 0.3–0.8, p = 0.002) and changing from rosuvastatin to another lipid lowering therapy (HR 2.2, 95% CI 1.4–3.5, p = 0.001) were independent predictors of AMI.

In this study, we assessed the rate and potential clinical risk of switching from the most effective available statin agent to another lipid modifying intervention in a primary care setting.

The analysis of a large primary care electronic medical record data resource revealed a surprisingly high rate of treatment substitution. More than 23% of patients were switched from the initially prescribed rosuvastatin 10–40 mg/day to another lipid lowering treatment during the observation period, without any evident clinical explanation. Actually, the decisions to switch from rosuvastatin to a potentially less effective intervention were taken by GPs, while the reasons for such a course of action in individual patients are not reported in the database. The only demographic and clinical factors associated with a higher probability of switching were female gender and presence of CKD. In particular, the higher likelihood of switch in patients with CKD suggests that safety concerns may have played a role in some instances [20]. Still, owing to the relatively low prevalence of renal disease in the study population (only 2%), such condition may have had just a limited impact on the overall results. As to female gender, published reports indicate that women may show an increased risk of developing muscle-related adverse symptoms associated with statin use [21]. Consequently, it is quite conceivable that some of the therapeutic substitutions, at least in women, may have been driven by side effects. Anyway, when considering the overall frequency of switching in the study population, it seems clear that the decision to change lipid- lowering therapy cannot be solely explained by plain clinical reasons. This appears even more evident when we take into account both the efficacy and the reassuring safety of rosuvastatin in clinical studies [22]. Moreover, no major potentially statin-related adverse clinical events (i.e., rhabdomyolysis or acute renal failure) have been recorded in the database for the study population.

In Italy, medication costs for cardiovascular prevention are covered by the National Health Service. However, similar to other European countries [23], Italian national and local Health Authorities have promoted specific policies in favor of switching from branded statins to generic alternatives during the study period (2011–2015) [13, 24]. It seems highly probable that these cost-cutting policies may have had a role in encouraging GPs to switch from rosuvastatin to other pharmacological agents, even in the absence of any significant clinical issue.

Another point of major interest emerging from this study is that switching from rosuvastatin treatment to other lipid lowering therapies was associated with a twofold higher probability of AMI during the observation period. Such relevant increase in cardiovascular risk was independent from all major demographic and clinical features. This result is consistent with previously reported observations supporting the notion that switching from more effective to less effective lipid lowering interventions may impart a higher probability of negative clinical outcomes in high risk clinical conditions [8]. Moreover, this evidence is also coherent with data from specific computer simulated clinical trials on rosuvastatin [9]. Overall, clinical studies have clearly shown that both LDL-C levels and cardiovascular outcomes are directly related to statin potency and dosing [2, 3].

In this study, most patients experienced a non-equipotent switch to less effective doses of less potent agents, clearly moving from “high” to “medium” or even “low” intensity statin therapy [19]. Even if LDL-C levels are not available in our series, it is reasonable to assume that this undue therapeutic modification may have altered lipid profile, thereby favoring a negative outcome. However, given the wide variety of different agents and dosages used for the therapeutic substitution, it is difficult to speculate about the real amount of LDL-C rise occurring in patients switched from rosuvastatin to other lipid lowering interventions.

Current clinical guidelines for cardiovascular prevention are clear in their recommendations regarding statin therapy and treatment targets [25]. In fact, clinical trials have shown that statins are more effective than placebo in reducing cardiovascular events, while for the same purpose an intensive statin therapy is more effective than a moderate one [2, 3]. Besides, the lowest risk is associated with the lowest LDL-C levels [2, 3, 15]. However, in clinical practice, patients at high cardiovascular risk are prone to be undertreated, while observational studies suggest that mandatory statin substitution may increase the gap between achieved and recommended therapeutic targets [23, 26]. In general, all statin interchange programs promoting the use of non-equipotent agents have been invariably associated with unfavorable patient outcomes [26‐28].

Overall, the results of this study confirm all the previous observational studies on the negative implications of non-equipotent switch on clinical cardiovascular outcomes.

We conclude that switching from rosuvastatin to another, potentially less effective, lipid lowering treatment may impart an increased risk of experiencing an AMI and should be avoided unless strictly necessary on clinical grounds. Moreover, this analysis supports the assertion that cost-containing therapeutic substitution programs should always employ clinically equivalent treatment alternatives.