Take-home Messages
The recently published ACC/AHA cholesterol guidelines recommend fixed-dose statin therapy for those at risk, and although not recommended as first line therapy, nonstatin therapies are recommended when less than anticipated therapeutic response to statin therapy occurs or when patients are not able to tolerate statin therapy. Nonstatin cholesterol-lowering drugs shown to reduce atherosclerotic cardiovascular disease (ASCVD) events in randomized controlled trials (RCTs) are preferred. No evidence was found to support the use of specific low-density lipoprotein (LDL)-cholesterol target levels.
Current clinical practice varies considerably from the updated recommendations: 32.4% of patients with an indication for statins under the new cholesterol guidelines were not currently receiving them, according to an analysis of the PINNACLE registry. In addition, 22.6% were receiving nonstatin therapies.
Efforts to implement the new cholesterol guidelines will result in significant increases in statin use, as well as significant reductions in cholesterol-lowering therapies without proven benefit in RCTs.
Background
For generations, clinical decision making has been based on training and experience. Recently, a new paradigm is reshaping clinical practice: decision making should be evidence based. This concept was put forward 15 years ago as a strong recommendation by the Institute of Medicine in its report “Crossing the quality chasm: a new health system for the 21st century” [1].
In brief, the concept states that patients should receive care based on the best available scientific knowledge. Usually this evidence is found in the form of a randomized controlled trial (RCT). When such knowledge is present, based upon RCT results, recommendations can be structured so that patient care will not vary illogically from clinician to clinician or from place to place based upon opinion or “experience.”
Evidence on how training and experience have been the main drivers of cardiovascular practice is found in a 2009 analysis of ACC/AHA guidelines in which all recommendations dating back to the first ACC guideline in 1984 were analyzed regarding their supporting evidence base [2]. In reviewing the 16 current guidelines in 2009, only 314 of a total of 2711 recommendations were classified as level of evidence A (median: 11%), meaning they were based on evidence from multiple randomized trials or meta-analyses. On the other hand, 1246 (median: 48%) recommendations had a level of evidence of C, meaning they were based on expert opinion, case studies, or standards of care.
Limiting consideration to those recommendations listed as Class I – meaning evidence and/or general agreement that a given procedure or treatment is useful and effective – only 245 of 1305 recommendations had a level of evidence A (median: 19%).
In other words, in 2009, a large proportion of guideline recommendations were based on lower levels of evidence or expert opinion. To remedy this, the authors called for a streamlining of clinical trials, more focus on areas of deficient evidence, and expanded funding for clinical research. In addition, they suggested that “the process of developing guidelines needs to be improved and that clinicians exercise caution when considering recommendations not supported by solid evidence.”
The current 2013 ACC/AHA guidelines for treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) risk in adults [3] were disruptive when they were released owing to their change away from treatment using the low-density lipoprotein (LDL)-cholesterol targets of previous iterations. The ACC/AHA guidelines committee noted that in a review of 19 RCTs, they found no data supporting treatment or titration of cholesterol-lowering therapy to specific LDL-cholesterol or non-HDL cholesterol goals in adults with ASCVD. All of the evidence was dose-related, with not one RCT that evaluated treatment of patients to specific treatment goals of >100 mg/dL or >70 mg/dL. Thus the new recommendations strongly based on evidence from RCTs now center on fixed-dose statin therapy.
What are the implications? Recently, the ACC PINNACLE registry was used to assess the potential impact of the new 2013 ACC/AHA cholesterol guidelines on lipid-lowering treatment and LDL-cholesterol testing patterns [4]. They determined that the majority of patients in the PINNACLE registry qualify for statin therapy under the new guidelines, primarily for secondary prevention of cardiac events. However, 32.4% of these patients were not receiving statin therapy. In addition, 22.6% were receiving nonstatin therapies, including 3.1% who were receiving nonstatins as their sole lipid-lowering therapy. Repeat or follow-up LDL-cholesterol testing occurred in 20.8% of patients.” Thus there was incomplete information on response to lipid-lowering therapy for the majority of patients.
Although the guidelines panel did not find evidence to support the use of nonstatin lipid-lowering therapies, while the cholesterol guidelines do not make a Class I recommendation of nonstatin therapies for routine risk reduction of ASCVD, in fact there is an entire section on nonstatins. Indeed, the guidelines expressly state, “Clinicians treating high-risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of nonstatin cholesterol-lowering therapy.” As has been pointed out in a letter to JACC [5], “high-risk” individuals include those with ASCVD, those with LDL-cholesterol ≥190 mg/dL, and those with diabetes 40–75 years of age with a 10-year risk of >7.5% for cardiovascular events. In this situation, the guideline recommends clinicians preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions and consider patient preferences.
The guideline panel members disagreed with the conclusion by Maddox et al. [4] regarding the charge that following the guidelines will lead to far less lipid testing. On the contrary, the guidelines endorse follow-up lipid assessment, especially LDL-cholesterol. They wrote in JACC [5] “Follow-up lipids are needed to not only determine attainment of the therapeutic response to the appropriate intensity of statin, but also to monitor adherence to statin and lifestyle therapy.”
It is important to correct this misunderstanding. The guidelines recommend a baseline lipid assessment before initiating statin therapy, then again 4–12 months after statin initiation, and every 4–12 months thereafter as indicated. This allows the clinician to check on adherence to the recommended therapies. Expected response is roughly 50% LDL-cholesterol lowering on intensive therapy and 30–50% reduction of LDL-cholesterol on moderate therapy. In the absence of such changes the patient should first be questioned about adherence to recommended therapy and diet. If no problems are found in these areas it may be necessary to increase the statin dose or use additional LDL-cholesterol lowering therapy. Thus the guideline does not do away with following lipid panels but it focuses first-line therapy on use of statin in doses known to have maximal patient benefit with addition of other therapies when expected changes in the lipid panel do not occur. The additional therapies should be used in a manner which reflects known clinical outcomes as the first choice.
Changing Clinical Management
Overall, the findings from ACC PINNACLE do suggest significant gaps in secondary prevention for contemporary cardiac patients. The implementation of the new cholesterol guidelines will prompt significant changes in current patient management. For example, if the 377,311 eligible patients in the PINNACLE population not currently receiving statin therapy were to receive statins as recommended by the guideline changes, those patients would be expected to experience a 25% reduction, on average, in cardiovascular events. This benefit would be especially pronounced among those with diabetes or an estimated ASCVD risk ≥7.5, who had the highest rates of nonstatin use (36.2% and 36.6%, respectively).
Finally, as the number of nonstatin lipid-lowering therapies is reduced, the side effects of lipid-lowering therapies (especially myopathic symptoms, which have a higher incidence among patients treated with both statins and either fibrates or niacin) would be expected to decline. In addition, among those patients who had no risk criteria, 48.6% were currently receiving statin therapy, which may no longer be indicated under the new guidelines.
The Bottom Line
Achieving concordance with the 2013 ACC/AHA cholesterol guidelines in patients treated in U.S. cardiovascular practices will result in:
significant increases in appropriate statin therapy resulting in improved cardiovascular outcomes,
better identification of patients at risk who could benefit from lipid-lowering therapies and,
significant reductions in use of nonstatin therapies for which proven clinical outcomes have not been established.