Atherosclerosis reversal possible with Crestor
ASTEROID achieves 0.79-percent reduction in percent atheroma volume
The progressive accumulation of cholesterol plaques in the coronary arteries portends a grim fate: an increased risk for coronary-artery disease (CAD) and myocardial ischemia. In recent years, the need to eliminate this risk has resulted in efforts to stop (or at least slow down) the atherosclerotic process-through aggressive treatment with lipid-lowering agents. Whether more drastic decreases in low-density-lipoprotein (LDL) and corresponding increases in high-density-lipoprotein (HDL) levels lead to regression of atheroma remained unanswered-until last year's publication of ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) in the Journal of the American Medical Association.
"Previous trials of statin did show progression can be halted or slowed down. But, with lower levels of LDL with rosuvastatin, regression can happen.... With reduction of your LDL to as low as 60 mg/dL, coronary-artery disease can be regressed by medical intervention," said Dr. John Añonuevo, associate professor from the University of the Philippines-Philippine General Hospital. Speaking in a symposium organized byAstraZeneca Philippines during the joint convention of the Philippine Society of Hypertension and the Philippine Lipid and Atherosclerosis Society, Añonuevo said rosuvastatin 40 mg "is the only statin that was able to show this regression (in atheroma burden) at this point in time."
Is regression possible?
Statins, the most extensively studied antidyslipidemic agents, are potent reducers of LDL levels. Studies over the past two decades have firmly established that greater reductions in bad-cholesterol levels spell reduced risk for cardiovascular events.
The TNT (Treating to New Targets), PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy), 4S (Scandinavian Simvastatin Survival Study), CARE (Cholesterol and Recurrent Events Study), HPS (Heart Protection Study), and LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trials have demonstrated that lower LDL levels meant less risk for future coronary events among patients with previous coronary heart disease. The results of these secondary-prevention trials are mirrored in primary-prevention studies such as WOSCOPS (West of Scotland Coronary Prevention Study), AFCAP (Air Force Coronary Atherosclerosis Prevention Study), and ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial).
Said Añonuevo: "There is a linear correlation between the level of LDL and the occurrence of cardiovascular events. That is why … we always want to achieve the lower LDL level."
Target LDL levels remain highly controversial, although lower levels do translate to better outcomes: clinically, there is less risk for future coronary episodes in patients with and without previous heart disease; and anatomically, recent investigations show a slowing down of the progression of the atherosclerotic process. The REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial demonstrated that intensive treatment with atorvastatin yielded greater reductions in LDL levels compared with moderate treatment with pravastatin. Moreover, aggressive management with atorvastatin halted atherosclerotic progression, as measured by the atheroma burden on intravascular ultrasound.
Said Añonuevo: "Before the ASTEROID came out, [the REVERSAL study] achieved the best reduction in LDL level to about 79 mg/dL.... At the same time, REVERSAL using atorvastatin did show that it can halt progression of coronary-artery sclerosis. There has been no documented regression, but REVERSAL did show you can delay the progression of atherosclerosis."
With the publication of the STELLAR (Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses) and ASTEROID, rosuvastatin emerged as the most potent among statins. "In the STELLAR trial, [rosuvastatin achieved] the greatest reduction in LDL, plus a significant increase in HDL. Now, ASTEROID was able to show that rosuvastatin is the first and only statin to show regression of atherosclerosis."
ASTEROID sought to determine whether intensive treatment with rosuvastatin leads to regression of coronary atheroma volume among patients with CAD. Previous studies have established that progress can be delayed and even halted, but regression has never been convincingly documented. Coronary-angiography studies show that at least 40-percent reduction in LDL levels is necessary to delay progress of arterial stenosis. Whether decreases of more than 40 percent in LDL levels will translate to regression of atheroma burden was the problem addressed by the trial.
ASTEROID landing
Using intravascular ultrasound (IVUS), the investigators measured percent atheroma volume (PAV) before and after 104 weeks of intensive treatment with rosuvastatin 40 mg/d. Change in total atheroma volume (TAV) in the most severely diseased 10-mm segment of the atheromatous artery (a primary end point with the PAV; the nominal change in TAV), as well as in the entire target artery (called normalized TAV), before and after treatment were also measured. Serial lipid measurements were done and baseline and posttreatment values were compared.
Before IVUS, coronary angiography was the diagnostic tool used to determine the patency of coronary vessels. Añonuevo said IVUS is better in determining whether there is regression of atherosclerosis, noting that while coronary angiography has been widely used to measure luminal narrowing, "it can underestimate atherosclerotic burden."
IVUS is done on patients who have undergone coronary angiography. The ultrasound transducer is introduced into the coronary catheter and the artery of interest is visualized from its most distal to its most proximal segments at one-mm slices. A complete picture of the artery from the inside is thus obtained.
Diseased segments that appear normal on angiography are better visualized on IVUS. "When you talk about atherosclerosis, it is nicer to look at the lumen of these patients," added Añonuevo. "IVUS allows a very good tomographic assessment of luminal area, plaque size, and composition, and that is why IVUS is used in this trial (ASTEROID)."
ASTEROID showed that the lipid profile of patients with preexisting coronary-artery disease significantly improved with intensive rosuvastatin treatment. Notably, there was a 53.2-percent change in LDL value from baseline-130.4 mg/dL pretreatment to 60.8 mg/dL posttreatment. Triglyceride and total-cholesterol levels also decreased by 14.5 percent and 33.8 percent, respectively. HDL levels, on the other hand, increased by 4.7 percent from 43.1 mg/dL at baseline to 49.0 mg/dL after treatment.
"So far, this has been the highest reduction in LDL level among all major trials of statins," pointed out Añonuevo. He added that the significant reduction in LDL and the increase in HDL are "a very good combination."
Improvement in the lipid profile of the patients was correlated to decreases in their atheroma burden. For ASTEROID, the PAV and TAV values were obtained using the recommendations set by the European College of Cardiology. The atheroma volume was computed by subtracting the lumen's cross-sectional area from the external elastic membrane's cross-sectional area; simple manipulations of this value yielded the PAV, the nominal change in TAV, and normalized TAV. The posttreatment values for these three efficacy parameters attest to rosuvastatin's capacity to cause regression of atherosclerosis.
"For the primary end points … a negative value (for the PAV) would mean that the atheroma value would decrease at the end of the study. True enough, the median percent of atheroma volume did show a 0.79-percent reduction at the end of the study," said Añonuevo. This makes ASTEROID "the first trial among statins to have documented a significant regression in coronary-artery disease."
He added: "The other primary end point, which is the total atheroma volume in the most diseased segment, there was a reduction (in the TAV) of 9.1 percent."
As for the secondary end point-the entire segment measurement of the total atheroma volume (normalized TAV)-there was a 6.8-percent reduction, all of which showed a significant reduction or regression of atherosclerosis. This means that four out of every five subjects enrolled in the study experienced regression of their atheroma burden with very-high-intensity statin treatment.
Rosuvastatin's safety was also found to rival those of the other statins. Although creatinine kinase and transaminase elevations were noted, these were expected changes and were within acceptable limits. In fact, a meaningful assessment of adverse events was not possible because very few subjects experienced significant adverse reactions. There were also no cases of rhabdomyolysis.
There were a few cases of drug discontinuations for varied reasons (musculoskeletal complaints, gastrointestinal complaints, neoplasms, increased creatinine kinase, increased ALT or bilirubin, and cardiovascular diseases).
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