http://www.medscape.org/viewpublication/30113 Treatment vs Risk: Updated Look at ACC/AHA Statin Guidelines.

CLINICAL CONTEXT

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for cholesterol management defined new eligibility criteria for statin treatment. It was previously undetermined whether the new criteria would improve identification of adults at greater risk for cardiovascular events. The goal of the longitudinal, community-based cohort study was to determine whether the ACC/AHA guidelines better identify persons in whom incident cardiovascular disease (CVD) develops or who have coronary artery calcification (CAC), compared with the National Cholesterol Education Program's 2004 ATP III guidelines.

A second study used a microsimulation model and large databases to estimate the cost-effectiveness of various 10-year atherosclerotic CVD (ASCVD) risk thresholds that could be used in the ACC/AHA cholesterol treatment guidelines.

STUDY SYNOPSIS AND PERSPECTIVE

Two new studies published this week address the new ACC/AHA guidelines for statin eligibility, with investigators concluding the new guidelines are better than previous iterations for identifying patients at increased risk for CVD^[2] and that the risk threshold used to initiate statins in primary prevention is worth the expended financial costs of long-term therapy.^[2]

Both papers, published July 14, 2015, in the Journal of the American Medical Association, answer questions about what patients will benefit from statin therapy and whether such treatment is cost-effective given the now-lower threshold for starting therapy, according to an editorial.^[3]

"Available evidence indicates that statins are both effective and cost-effective for primary prevention even among low-risk individuals," write Dr Philip Greenland (Northwestern University Feinberg School of Medicine, Chicago, IL) and Dr Michael Lauer (National Heart, Lung, and Blood Institute, Bethesda, MD). "Although lifestyle interventions must be employed across all segments of the population, for many people a statin drug will also be required to minimize risk."

Overall, say the editorialists, the two studies provide evidence to justify the pooled cohort equation within the new ACC/AHA guidelines for assessing risk as well as the recommended treatment thresholds.

As reported previously by heartwire from Medscape, the 2013 ACC/AHA cholesterol guidelines abandoned the low-density lipoprotein cholesterol treatment targets and instead focus on treating primary- and secondary-prevention patients with a moderate- or high-intensity statin depending on their risk of cardiovascular events. Most important, and perhaps controversially, the new guidelines recommend treating individuals without evidence of CVD or diabetes but who have low-density lipoprotein cholesterol levels between 70 and 189 mg/dL and a 10-year risk of ASCVD ≥7.5%.

"Some of the controversy with the new guidelines, at least from my take on it, is that we're diluting the patient population who are now getting statins, that we're making people statin eligible who are not at higher risk," Dr Udo Hoffmann (Massachusetts General Hospital, Boston, MA), senior investigator of the study comparing the new guidelines against the older 2004 treatment recommendations, told heartwire .

Dr Thomas Gaziano (Brigham and Women's Hospital, Boston, MA), who led the cost-effectiveness analysis along with Dr Ankur Pandya (Harvard School of Public Health, Boston, MA), added that the concern with the new guidelines was that the risk threshold was simply too low at 7.5%, which would translate into many more people treated with statin therapy. While the first paper deals with statin eligibility and cardiovascular risk, they focused on assessing the cost-effectiveness of the medications in primary prevention given that statins are now available cheaply as generics.

The Main Event: ATP III vs ACC/AHA Cholesterol Guidelines

In the first paper, Hoffmann, along with lead investigator Dr Amit Pursnani (Massachusetts General Hospital, Boston), used data from the Framingham Heart Study to determine whether the 2013 ACC/AHA guidelines improved the identification of individuals who went on to develop incident CVD when compared with the 2004 National Cholesterol Education Program's Adult Treatment Panel (ATP) III recommendations for statin therapy.

In the Framingham Heart Study cohort, which included patients who underwent multidetector computed tomography (CT) for CAC screening and were followed for 9.4 years, the researchers identified 2435 statin-naive patients. Based on the ACC/AHA threshold for statin therapy, 39% were eligible for a statin, while just 14% were eligible for treatment using the older ATP III guidelines.

Over the follow-up period, the researchers observed that even though more than three times as many patients were eligible for statins with the new criteria, those eligible for statin therapy using the ACC/AHA guidelines had a significantly higher risk of incident CVD compared with those eligible for statins using the older guidelines.

Using the 2004 ATP III guidelines, 24 CVD events occurred in 348 statin-eligible patients (6.9%) compared with 50 clinical events among 2087 non-statin-eligible patients (2.4%). As a result, using the older guidelines for therapy decisions, those eligible for a statin had a threefold increased risk of CVD compared with those not eligible for a statin.

With the 2013 ACC/AHA guidelines, on the other hand, 59 cardiovascular events occurred in the now-expanded population of 941 statin-eligible patients (6.3%). Comparatively, just 15 events occurred in 1494 patients not eligible for statins (1.0%). Overall, the risk of CVD among the eligible patients using the ACC/AHA guidelines was nearly seven times higher than those not eligible for statin therapy.

To heartwire , Hoffmann said the cardiovascular event rate between the 2004 and 2013 guidelines are almost identical--6.9% using the 2004 criteria vs 6.3% using the ACC/AHA guidelines--suggesting physicians are not diluting the patient population who are given the lipid-lowering drugs. "The fear was that if we treated more patients with statins the event rate would drop down to 4%," said Hoffmann. "This means that the people who are newly statin eligible would have been at much lower risk. That would have then changed the risk/benefit profile of taking a statin considerably."

In their analysis, approximately one-third of the 2435 patients were considered intermediate risk, defined as having a 10-year Framingham Risk Score of 6% to 20%. Of these patients, 80% were eligible for statins using the 2013 ACC/AHA guidelines compared with 27% using the 2004 recommendations. Similarly, the risk of incident CVD among statin-eligible vs noneligible patients was significantly higher when the 2013 eligibility criteria for statin therapy were applied. In contrast, there was no difference in events among the eligible vs noneligible statin patients using the older guidelines.

Finally, the researchers validated their findings using an actual marker of atherosclerosis. Individuals with CAC on CT were significantly more likely to be treated with a statin using the new guidelines. For those with a CAC score >100, 80% of these patients would be eligible for a statin using the new guidelines vs 32% using ATP III. For those with a CAC score >300, 85% and 32% would be eligible for statins using the new and older guidelines, respectively.

"It gives us some reassurance about what we're seeing," said Hoffmann in reference to the CAC data supporting the new statin eligibility data.

The bottom line, said Hoffmann, is that the new guidelines triple the number of patients eligible for statin therapy, but this larger group of patients has a similar relative risk of CVD as those eligible under the 2004 clinical guidelines. Overall, within their cohort, 593 additional patients in the Framingham Heart Study would have been eligible for statins using 2013 guidelines compared with the 2004 recommendations. These patients had an incident CVD event rate of 5.7%, said Hoffmann.

The Cost-effectiveness of Statins

Regarding the cost-effectiveness of drug therapy, Gaziano said that in previous iterations of the cholesterol guidelines, including the ATP III recommendations, the risk threshold for starting treatment was based on benefit but also on cost. In the past, though, statins were patented medications and cost many orders of magnitude more than what they cost today.

Using a microsimulation model that incorporated lifetime treatment and health outcomes, among other variables, in a group of one million hypothetical individuals aged 40 to 75 years, Pandya, Gaziano, and colleagues estimated the cost-effectiveness of various 10-year ASCVD risk thresholds that could be used in the ACC/AHA cholesterol treatment guidelines. While treatment is recommended for patients with a 10-year risk ≥7.5%, Pandya explained they used 12 treatment thresholds, everything from a 10-year risk ≥30% to as low as ≥1.0% for initiating treatment, to get a sense of the cost-effectiveness of the drugs in different settings.

In their base-case scenario, at the current threshold of 7.5% of greater, 48% of participants would be treated with statins. At this ASCVD risk threshold, the incremental cost-effective ratio (ICER) was $37,000 per quality-adjusted life-year (QALY) gained compared with the ASCVD threshold of 10% or higher. At the ASCVD treatment threshold of ≥5.0%, ≥4.0%, and ≥3.0%, respectively, the ICER was $57,000/QALY, $81,000/QALY, and $140,000/QALY gained compared with the 10% ASCVD treatment threshold.

Based on their assessment, statins are cost-effective at the ≥7.5% ASCVD treatment threshold and, depending on the metric used to define optimal cost-effectiveness for society (some analyses use thresholds of $100,000 or $150,000/QALY gained as cost-effective), are cost-effective using much more lenient 10-year ASCVD risk thresholds for initiating therapy.

"A lot of these numbers are somewhat arbitrary," said Gaziano, including the ≥7.5% threshold for starting statins. Other trials have shown that patients with an even lower 10-year risk of ASCVD benefit from treatment. They believe the current ACC/AHA threshold for starting therapy is not controversial given the benefit of therapy and the associated cost-effectiveness at this threshold.

In their analysis, the researchers also incorporated the "disutility," or the loss of quality of life, associated with taking a statin into their model. The disutility of taking the statin daily did affect their results, said Gaziano. For a patient at lower risk for cardiovascular events, Gaziano said physicians should be aware of this effect and to ask patients "how much do you dislike taking a medication?" beyond the impact of side effects.

"If that's a real bother for them, they might not take it anyway, and I would want to know that, if they are going to be compliant with the medication," he said. For those lower-risk patients with a real aversion to statins, other lifestyle interventions might be a better focus.

Hoffmann discloses receiving grants from HeartFlow, Siemens Healthcare, Genentech, and the American College of Radiology Imaging Network and personal fees from the AHA. Gaziano discloses grant support from the National Institutes of Health. Pandya discloses grant support from the National Institutes of Health. All other study authors have disclosed no relevant financial relationships. Greenland is a senior editor of JAMA and discloses grant support from the National Heart, Lung, and Blood Institute. Lauer is an employee of the National Heart, Lung, and Blood Institute.

References

1. Pursnani A, Massaro JM, D'Agostino RB, et al. Guideline-based statin eligibility, coronary artery calcification, and cardiovascular events. JAMA 2015; 314:134-141.
2. Pandya A, Sy S, Cho S, et al. Cost-effectiveness of 10-year risk thresholds for initiation of statin therapy for primary prevention of cardiovascular disease. JAMA 2015; 314:142-150.
3. Greenland P, Lauer MS. Cholesterol lowering in 2015: Still answering questions about how and in whom. JAMA2015; 314:127-128.

STUDY HIGHLIGHTS

• Participants in the longitudinal cohort study came from the offspring and third-generation cohorts of the Framingham Heart Study, including 2435 statin-naive participants.
• Mean age was 51.3±8.6 years; 56% were women.
• Between 2002 and 2005, participants underwent multidetector CT for CAC.
• ATP III determined statin eligibility based on Framingham risk factors and low-density lipoprotein thresholds, whereas ACC/AHA used the pooled cohort calculator.
• Incident CVD was the main study end point, defined as myocardial infarction, coronary heart disease mortality, or ischemic stroke.
• Coronary heart disease and CAC (as measured by the Agatston score) were secondary end points.
• ACC/AHA identified 941 (39%) of 2435 statin-naive participants as being statin eligible, compared with 348 (14%) of 2435 identified by ATP III (P <.001).
• During follow-up for incident CVD (median duration, 9.4 years), there were 74 incident CVD events: 40 nonfatal myocardial infarctions, 31 nonfatal ischemic strokes, and 3 fatal coronary heart disease events.
• Compared with participants who were statin eligible by ATP III, those eligible by ACC/AHA had increased hazard ratios for incident CVD: 6.8; 95% confidence interval, 3.8-11.9 vs 3.1; 95% confidence interval, 1.9-5.0, respectively (P <.001).
• Findings were similar for CVD in participants with intermediate Framingham Risk Scores and for coronary heart disease.
• Among the 593 participants (24%) who were newly statin eligible, the incident CVD rate was 5.7%, resulting in a number needed to treat of 39 to 58.
• For participants with CAC, statin eligibility by ACC/AHA was greater than by ATP III: for a CAC score of more than 0 (n=1015), 63% vs 23%; for a CAC score of more than 100 (n=376, 80% vs 32%; and for a CAC score of more than 300 (n=186), 85% vs 34% (all P <.001).
• Among ACC/AHA statin-eligible participants (306/941 [33%]), a CAC score of 0 identified a low-risk group with a CVD rate of 1.6%.
• In the second study, the microsimulation model included lifetime time horizon, US societal perspective, 3% discount rate for costs, and health outcomes.
• Data sources for the model included National Health and Nutrition Examination Surveys, large clinical trials and meta-analyses for statin benefits and treatment, and other published data.
• The model assumed that hypothetical individuals from a representative US population aged 40 to 75 years received statins, experienced ASCVD events, and died of ASCVD-related or non-ASCVD-related causes based on ASCVD natural history and statin treatment parameters.
• Compared with an ASCVD threshold of 10% or greater, the current threshold of at least 7.5%, which was estimated to be associated with 48% of adults treated with statins, had an ICER of $37,000 per QALY.
• An ASCVD threshold of at least 4.0% (61% of adults treated) had an ICER of $81,000/QALY, and at least 3.0% (67% of adults treated) had an ICER of $140,000/QALY.
• The investigators estimated that changing from an ASCVD risk threshold of at least 7.5% to an ASCVD risk threshold of at least 3.0% would avert an additional 161,560 CVD events.
• Cost-effectiveness results were sensitive to changes in the disutility associated with taking a pill daily, statin price, and the risk for statin-induced diabetes.
• Using a cost-effectiveness threshold of $100,000/QALY, there was a more than 93% chance that the optimal ASCVD threshold was 5.0% or less, based on probabilistic sensitivity analysis.

CLINICAL IMPLICATIONS

• In a community-based, primary prevention cohort, ACC/AHA guidelines for determining statin eligibility offered greater accuracy and efficiency than ATP III in identifying increased risks for incident CVD and subclinical coronary artery disease, especially in intermediate-risk participants.
• A microsimulation model of US adults 45 to 70 years old showed acceptable cost-effectiveness at the current 10-year ASCVD risk threshold of 7.5% or more used in the ACC/AHA guidelines (ICER, $37,000/QALY). However, more lenient ASCVD thresholds would be optimal using cost-effectiveness thresholds of $100,000/QALY (≥4.0% risk threshold) or $150,000/QALY (≥3.0% risk threshold). The optimal ASCVD threshold was sensitive to patient preferences for taking a pill every day, changes in statin price, and the risk for statin-induced diabetes.
• Implications for the Healthcare Team: Members of the healthcare team should be aware that ACC/AHA guidelines can help identify which patients will benefit from statin therapy, and that preventive treatment is cost-effective at the now lower threshold for starting statins.