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March 08, 2018
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Lipid-lowering therapy for primary prevention of CV events: Navigating the guidelines

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A relative paucity of evidence guiding the use of statin therapy in the primary prevention of atherosclerotic CVD events has led to disparate treatment strategies recommended by various medical associations.

One guiding piece of literature for current treatment recommendations that supports the overall use of statin therapy in the primary prevention of atherosclerotic CVD is the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis. In the CTT analysis of 27 trials, statin therapy reduced the rate of nonfatal MI, CV death, coronary revascularization or stroke by 11 events per 1,000 patients treated for 5 years. The study additionally showed that as LDL was reduced, the proportional risk for major vascular events also decreased, ultimately leading to the push for higher-intensity statin therapy. However, the study did not define target LDL goals or optimal statin intensity, leading to some of the disparities in treatment goals between guidelines.

Joshua Jacobs, PharmD
Joshua Jacobs
Bonnie Kaminsky, PharmD, BCPS
Bonnie Kaminsky
Scott Yost, PharmD, BCPS
Scott Yost

Additionally, a 2016 systematic review of 19 randomized controlled trials depicted a reduction in major vascular events (RR = 0.7; 95% CI, 0.63-0.78) and all-cause mortality (RR = 0.86; 95% CI, 0.8-0.93) due to statin therapy. Most of the trials utilized moderate-intensity statin therapy, which also creates diversity among guideline recommendations.

Between the differing recommendations in the 2013 American College of Cardiology/American Heart Association blood cholesterol guidelines, the 2016 European Society of Cardiology/European Atherosclerosis Society (EAS) guidelines and the 2016 U.S. Preventive Services Task Force guidelines, confusion regarding optimal therapy can only be expected. All three guidelines support the use of statin therapy for primary prevention, but in terms of qualifications for initiation, doses and targets for therapy, the recommendations diverge greatly.

2013 ACC/AHA guidelines

The ACC/AHA guidelines deviated immensely from the prior Adult Treatment Panel (ATP III) guidelines, by steering away from cholesterol goals in favor of fixed-dose statin therapy based on patient risk classifications. The 10-year risk for fatal and nonfatal atherosclerotic CVD helped to further define patients within these risk categories. The 10-year risk for an atherosclerotic CVD event is calculated based on age, sex, race, HDL, total cholesterol, systolic BP, diabetes and smoking status. The four groups that qualify for statin therapy and the respective statin intensity are described in Table 1 (below).

With these broad patient groups, many patients with CV risk factors qualified for statin therapy thatpreviously did not under the ATP III guidelines. Some of the rationale behind initiating statin therapy without specific LDL targets, especially in patients with diabetes, was that patients may still be at high risk for an atherosclerotic CVD event with normal LDL levels. With treatment recommendations now based predominantly on risk factors, patients may qualify for moderate- or high-intensity statin therapy regardless of baseline LDL levels. Additionally, the ACC/AHA guidelines do not recommend nonstatin therapy for the primary prevention of atherosclerotic CVD events.

Source: Provided by the authors.
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2016 ESC/EAS guidelines

The ESC/EAS guidelines classify patients into CV risk categories utilizing the Systematic Coronary Risk Evaluation (SCORE) system; contrary to the ACC/AHA guidelines, treatment strategies still target LDL levels. The SCORE system estimates the 10-year risk for fatal atherosclerotic CVD events based on European region, age, sex, systolic BP, total cholesterol and smoking status. The four risk categories for primary prevention of an atherosclerotic CVD event and respective LDL targets are described in Table 2 (below).

Recommendations state to initiate statin therapy at the highest recommended dose, or tolerated dose, to reach the respective target LDL levels. If the target is not reached with statin monotherapy, combination therapy with a statin and ezetimibe, a bile acid sequestrant, or a PCSK9 inhibitor is recommended. Additional guidance is provided for patients with diabetes due to the increased inherent CV risk, including targets for LDL, non-HDL and apolipoprotein B levels.

2016 USPSTF guidelines

With the release of the 2013 ACC/AHA guidelines, prescribing of statin therapy, especially higher-intensity statin therapy for primary prevention of atherosclerotic CVD events, has been on the rise. The USPSTF guidelines address this potential rise in high-intensity statin prescribing patterns by limiting the recommendations based on age alone as a risk factor and avoiding the initiation of high-intensity statins altogether. Instead, the CV risk factors include dyslipidemia, diabetes, hypertension and smoking. The recommendations suggested by the USPSTF guidelines are described in Table 3 (below).

The recommendations excluded patients with familial hypercholesterolemia and do not address further considerations for patients with diabetes aside from considering it a CV risk factor. In addition, they did not conclude benefit from high-intensity statin therapy compared with low to moderate intensity due to the unclear benefit in the setting of primary prevention of atherosclerotic CVD events and potential adverse effects associated with high-intensity statin therapy.

In an analysis of the National Health and Nutrition Examination Survey from 3,416 U.S. patients, it was determined that implementation of the ACC/AHA guidelines recommendations would provide an additional 24.3% statin initiation compared with an additional 15.8% from the implementation of the USPSTF guideline recommendations. A portion of the gap between the guideline recommendations contained high-risk patients who were younger and with diabetes, but did not have a 10-year atherosclerotic CVD risk greater than 10%. Although the 10-year atherosclerotic CVD risk may be low, in high-risk younger patients the long-term atherosclerotic CVD risk beyond 10 years may still be high.

Table 2. 2016 ESC/EAS guidelines for primary prevention  of atherosclerotic CVD events with lipid-lowering therapy
Source: Provided by the authors.
Table 3. 2016 USPSTF statin treatment recommendations  for primary prevention of atherosclerotic CVD events
Source: Provided by the authors.
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Available guidance

Ultimately, current practice guidelines and evidence suggest a significant benefit of statin therapy for patients with or without diabetes at very high or high risk for atherosclerotic CVD events with 10-year risk estimates of 7.5% and higher. For the U.S. guidelines, there is also uniformity in not recommending therapy for primary prevention in individuals younger than 40 years or older than 75 years. Controversies on the benefit of statins for primary prevention in patients with diabetes and a 10-year atherosclerotic CVD risk of less than 7.5% still exist with little guidance on proper management.

Questions also remain regarding statin intensity and the need for LDL targets. The adaptation of a universal risk stratification system is difficult due to the varying risk factors between geographic region and baseline disease states. Cohesiveness between various groups in developing clearer recommendations for primary prevention of atherosclerotic CVD events is in order. Until then, the risk factors need to be evaluated on a patient-specific basis in deciding the proper use and goals of statin therapy for primary prevention of CV events.

Disclosures: Jacobs, Kaminsky and Yost report no relevant financial disclosures.