Greater CAD Progression in Poor Responders to Statin Therapy: One in Five Fail to Respond

February 27, 2015

CLEVELAND, OH — One in five patients with coronary artery disease receiving a statin failed to have a significant LDL-lowering response to treatment, and these patients experienced a significant progression of atherosclerosis over a follow-up period ranging from 18 to 24 months, a new analysis has shown[1].

Among those who failed to respond to statin therapy, LDL-cholesterol levels increased 6.2%, whereas those who responded to treatment saw their LDL cholesterol levels cut from 131 mg/dL to 73 mg/dL, a reduction of 44.5%. Regarding the serial change in atheroma burden as measured by intravascular ultrasound (IVUS), adjusted percent atheroma volume (PAV) decreased 0.21% among responders to therapy and increased 0.83% among those who failed to respond to treatment, a statistically significant difference.

"We know that plaque progression is associated with a higher risk of cardiovascular events," senior researcher Dr Stephen Nicholls (University of Adelaide, Australia) told heartwire . "We see much more progression in these patients. They need more aggressive therapy. Step number one is going to be to increase their statin dose. This supports ongoing monitoring. If doctors interpret 'prescribe and forget' as a principle for all statin doses, [patients] may still progress and still be at a high risk of events."

"Prescribe and forget" alludes to the latest American College of Cardiology (ACC)/American Heart Association (AHA) clinical guidelines for the management of cholesterol. In 2013, as has been noted, the ACC/AHA abandoned treating to LDL-cholesterol targets and instead encouraged physicians to prescribe either a moderate- or high-intensity statin depending on the patient's baseline risk. Critics of the guidelines have said the change might have the unintended effect of physicians prescribing statins without adequately determining whether they are having the desired effect on lowering LDL-cholesterol levels.

For their part, the ACC/AHA has said they still encourage monitoring to determine the extent of LDL lowering and to monitor compliance, but the clinical-trials data support the use of either a moderate- or high-intensity statin and not lowering LDL-cholesterol levels to a specific level.

To heartwire , Nicholls said there at least two concerns with the current ACC/AHA-treatment approach. "First, we wonder whether there are differences in LDL-lowering response with statin therapy, which might be affected by not checking," he said. "Second, I personally support the guidelines emphasis of high-intensity statin therapy for higher-risk patients, but the reality is clinical practice comprises significant inertia. Many doctors simply don't use high doses even in patients who are likely to derive the greatest benefit."

Mixed Data From Multiple IVUS Trials

In the present study, which is published February 26, 2015 in Arteriosclerosis, Thrombosis, and Vascular Biology with lead author Dr Yu Kataoka (Cleveland Clinic, OH), the researchers included 647 patients with coronary disease participating in seven clinical trials using serial imaging with IVUS. Of these, "hyporesponders" were defined as those who had a minimal response to statin therapy, that being a less than 15% reduction in LDL-cholesterol levels. The statins tested included rosuvastatin (Crestor, AstraZeneca), atorvastatin, simvastatin, and pravastatin, and compliance rates were high (more than 90% in the various studies).

Among the participants, 20% treated with a statin were identified as hyporesponders. These patients experienced a small increase in LDL cholesterol at follow-up despite treatment. The serial IVUS imaging showed that individuals who failed to respond to statin therapy had greater atheroma progression and less atheroma regression than the 80% of patients who responded to treatment.

Dr Roger Blumenthal (Johns Hopkins University School of Medicine, Baltimore, MD), who was not involved in the study, told heartwire that the large-scale, multicenter, randomized, controlled trials have shown statins not only reduce the risk of future atherosclerotic disease events by 25% to 45% but also slow the progression of atherosclerosis through lipid lowering and other anti-inflammatory effects.

For some time, physicians and researchers have been attempting to understand why some patients respond to treatment and others don't. The IVUS paper, he said, underscores the important point that nonresponders, or hyporesponders, are at an increased risk for future events.

"Once these patients are identified, routine monitoring of LDL cholesterol is reasonable, and developing a regimen that includes a statin and other lipid-lowering medication plus aggressive lifestyle modification that includes low dietary saturated-fat intake and increased aerobic exercise as well as great consumption of fruits and vegetables would be important," said Blumenthal.

Speaking with heartwire , Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas, TX) said that it remains important for physicians to monitor their patients after prescribing a statin. While they might not necessarily be treating to a specific LDL target, the goal is still a 50% reduction in LDL-cholesterol levels. "Prescribe and forget" is not appropriate, as there is another drug, ezetimibe (Zetia, Merck/Schering-Plough) that physicians can prescribe if the patient isn't getting the desired reduction in LDL, he noted.

"Now there is something we can do about it," said de Lemos. "In some patient populations, another drug might be of benefit."

For de Lemos, when faced with a nonresponder to statin therapy, his first thought is the patient isn't taking the medication. If it turns out they are, the second step is to maximize the dose. If they fail to respond to the high dose, then he will consider adding ezetimibe.

The jury had been out on ezetimibe for a long time, but data from the IMPROVE-IT study were finally published in November 2014. That trial showed the addition of ezetimibe to simvastatin 40 mg in post-ACS patients reduced the risk of cardiovascular events by a modest 6.4% compared with simvastatin alone.

There is also great excitement about PSCK9 inhibitors, a new class of LDL-lowering drug that works via a mechanism different from statins. Some of the drugs in advanced testing include evolocumab (Amgen), alirocumab (Regeneron Pharmaceuticals), and bococizumab (Pfizer).

Kataoka has disclosed no relevant financial relationships. Nicholls has received speaking honoraria from AstraZeneca, Pfizer, Merck Schering-Plough, and Takeda; consulting fees from AstraZeneca, Abbott, AtheroNova, Esperion, Amgen, Novartis, Omthera, CSL Behring, Boehringer Ingelheim, Pfizer, Merck Schering-Plough, Takeda, Roche, Novo Nordisk, LipoScience, and Anthera; and research support from Anthera, AstraZeneca, Cerenis, Eli Lilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience. Disclosures for the coauthors are listed in the article. de Lemos acknowledges grant support from Roche Diagnostics and Abbott Diagnostics and has consulted for Diadexus. Blumenthal reports no relevant financial relationships.

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