On Tuesday last week the American College of Cardiology and the American Heart Association published in both the Journal of the American College of Cardiology and Circulation the manuscript of new clinical practice guidelines for primary and secondary prevention to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). The ASCVDs described in the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk, included coronary heart disease (CHD), stroke and peripheral artery disease (PAD), given their origin is presumed to be atherosclerotic. The recommendations for the treatment of blood cholesterol levels were composed using data from randomized controlled trials (RCTs), meta-analyses and systematic reviews of RCTs.

What are the changes in the new guidelines?

Since the update of Adult Treatment Panel III (ATPIII) in 2004, the main biomarker to gauge success in atherosclerosis treatment had been a LDL-C level below 70mg/dL and between 70 and 130mg/dL (depending on the kind of patient) and a non-HDL-C level between 100 and 199 mg/dL, for those over age 21. A reduction in LDL-C has been thought to slow disease progression by preventing the hardening and narrowing of the arteries that is characteristic of ASCVD. In a turn of events, the newly published guidelines made no recommendations for specific LDL-C or non-HDL-C goals in primary or secondary prevention of ASCVD. The idea is to focus instead on patient populations in which statin therapy would be the most beneficial, such as those perceived to be at an elevated risk of cardiovascular events, including those with lower LDL-C levels. The patient groups highlighted in the guidelines included:

  • Patients with clinical ASCVD
  • Patients with primary elevations of LDL-C over 190 mg/dL (such as those with familial hypercholesterolemia)
  • Patients diagnosed with type 1 or 2 diabetes, aged 40 to 75 years old with LDL-C between 70 and 189 mg/dL and without clinical ASCVD
  • Patients without clinical ASCVD or diabetes with LDL-C levels between 70 and 189 mg/dL and estimated 10-year ASCVD risk of 7.5 percent or higher

In comparison to the old ?lowest is best? strategy in terms of LDL-C blood levels, it has now been proposed that reducing this parameter around 30-50 percent from baseline is sufficient to demonstrate a reduced risk of ASCVD. To achieve this goal the panel recommended to basically follow the theme ?the more, the better? by implementing a more aggressive and broader statin treatment strategy depending on the risk category the patient fits into. One example could be a high dose statin therapy (atorvastatin 80mg per day) to lower the LDL-C levels by approx. 50 percent or a moderate intensity statin therapy (atorvastatin 20mg per day) to reduce levels by approx. 30-50 percent.

What impact could the new guidelines have on the treatment of patients?

One benefit of these newly issued guidelines is that they will begin to address the issue of establishing a more individualized approach to treatment. This is especially important in the ASCVD population, which is highly heterogeneous with respect to the etiology of the disease and long term outcomes. This heterogeneity has been partially addressed in the guidelines by identifying patients deemed most likely to benefit from statin therapy according to their cardiovascular risk. However, this risk calculator is already coming under criticism for overestimating risk of myocardial infarction and stroke by 75 percent to 150 percent and not taking into account other well established cardiovascular risk factors such as body mass index.

By eliminating strict LDL-C goals and expanding the definition of patients that are perceived to be at high cardiovascular risk, could the new guidelines be thought of as less stringent but more widely applicable? Indeed, the entire purpose of these radical changes in this proposed treatment paradigm is to target a broader patient population in order to prevent cardiovascular events from happening in the first place. Enforcement of these guidelines will have a large impact on how patients are treated by tailoring the intensity of statin treatment to their individual risk, but we could see bigger changes involving the number of patients treated with statins because patients without clinically evident ASCVD are now being targeted for treatment.

What impact will these guidelines have on the dyslipidemia market?

There is talk that implementation of these guidelines could result in an eventual doubling of patients treated with statins. The conditions for incorporating more widespread use of statins seem to be particularly favorable when looking at the dyslipidemia market landscape, with generic versions of Pfizer's Lipitor and Merck's Zocor now available and with generic versions of AstraZeneca's Crestor expected from 2016. More importantly, the new guidelines could mean that non-statin LDL-lowering therapies may have to take a back seat. Statins are indeed being favored in the guidelines for their reductions in cardiovascular events, which were associated with reductions in LDL-C. However, the benefits of statins may extend beyond their LDL-C reducing capabilities and some evidence suggests the involvement of an anti-inflammatory mechanism. The guidelines express that there are not any proven benefits associated with the use of Merck's Zetia (ezetimibe) or any niacin therapy in primary or secondary prevention of ASCVD. Trials like AIM-HIGH and HPS2-THRIVE studied the impact of adding niacin on top of statin therapy on non-HDL-C levels and showed that there is no further ASCVD risk reduction in individuals with LDL-C levels of 40-80 mg/dL. Trials such as IMPROVE-IT, which is investigating Merck's ezetimibe and simvastatin combination (Vytorin), should test the potential benefits of such add-on therapies and further assess the validity of the LDL-C hypothesis. But what does this mean for highly anticipated emerging therapies like the CETP inhibitors and the PCSK9 inhibitors?

There is now ramped up speculation as to whether these novel therapies will gain approval. While these new guidelines reduce chances for approval merely on the basis of changes in surrogate end points, reductions in ischemic events in the large cardiovascular outcomes trials should ensure more widespread uptake of these agents than initially thought because these new therapies are being investigated on top of statin therapy. Therefore, by increasing the number of statin treated patients, we could see an expansion in the patient population that could potentially receive these novel therapies. There is also considerable room for uptake of novel lipid modifying therapies among statin-intolerant patients and patients that are refractory with treatment by a statin. However, should the LDL-C hypothesis not hold up in these outcomes trials, considerable opportunity could open up for therapies targeting different aspects of atherosclerosis, such as those targeting inflammation.

In-depth analysis of therapies being developed for ASCVD, with accompanying epidemiology driven sales forecast models, is presented in a number Decision Resources? Pharmacor reports. These include: Acute Coronary Syndrome (Event Driven); Dyslipidemia (Event Driven); Atherothrombotic Diseases (expected publish date December 2013).

Business Insights Analyst Joseph Dwyer, M.Res., Ph.D., and Data Analyst Stefanie Matlok are part of the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

What drives the therapy selection test market?

View Now