Cleveland, OH - Patients with coronary artery disease (CAD) who reduce LDL cholesterol to very low levels and achieve a normal systolic blood pressure have the slowest progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS), a new study has shown [1]. The findings, according to investigators, support the need for intensive management of global risk in patients with CAD.
"What's happened in recent years with the advent of more potent statins and all the education done around that is that getting people to LDL goal is achieved fairly well," senior investigator Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "But getting people to dual goals is not done well around the country. We wanted to tell people that there really is some pretty good evidence here that if you get your blood pressure down to normal and your LDL down below 70, this is a disease that can not only be halted, but potentially can even regress."
The results of the study are published in the March 24, 2009 issue of the Journal of the American College of Cardiology.
Seven studies rolled into one
To clarify the relationship between LDL cholesterol and systolic blood pressure and their effects on coronary plaque progression, the researchers, led by Dr Adnan Chhatriwalla (Cleveland Clinic) studied 3437 patients with established CAD enrolled in seven clinical trials. The studies included REVERSAL, CAMELOT, ACTIVATE, ASTEROID, ILLUSTRATE, PERISCOPE, and STRADIVARIUS, a group of trials that investigated statins, acyl coenzyme A:cholesterol acyltransferase (ACAT) and cholesteryl ester transfer protein (CETP) inhibitors, rimonabant, ACE inhibitors, and calcium-channel blockers, among others.
Patients were stratified into four groups based on their average on-treatment LDL-cholesterol levels and systolic blood pressure:
- LDL cholesterol <70 mg/dL and systolic blood pressure <120 mm Hg.
- LDL cholesterol <70 mg/dL and systolic blood pressure >120 mm Hg.
- LDL cholesterol >70 mg/dL and systolic blood pressure <120 mm Hg.
- LDL cholesterol >70 mg/dL and systolic blood pressure >120 mmHg.
Changes in atheroma burden were monitored by IVUS, which was measured at baseline and at 18 to 24 months.
Patients with very low LDL-cholesterol levels and normal systolic blood pressure, group 1, had the least progression in percent atheroma volume (PAV) and total atheroma volume (TAV). In addition, these patients also had less frequent atheroma progression and more frequent regression. In patients with systolic blood pressure >120 mm Hg who still had very low LDL cholesterol levels, group 2, less progression of PAV and TAV was also observed.
"It really makes a big difference if you can get both down," said Nissen. "It's a big payoff for patients if physicians are diligent about getting LDL and blood pressure under control."
Among patients with LDL-cholesterol levels >70 mg/dL, normal systolic blood pressure was associated with no greater reduction in PAV or TAV, suggesting that lipid lowering has a larger impact than blood-pressure control on plaque progression, findings supported by recent clinical trials.
The findings challenge current treatment recommendations for hypertension, noted Nissen, and he recommends treating prehypertensive patients with coronary disease, those with pressures of 120 to 139 mm Hg systolic or 80 to 89 mm Hg diastolic. In the CAMELOT study, he points out, the calcium-channel blocker amlodipine decreased the risk of cardiovascular events in patients with CAD and normal blood pressure, as did the ACE inhibitor enalapril, but to a lesser extent.
"Remember that these are all people who have coronary artery disease," said Nissen. "These are not your typical primary-prevention patients with hypertension. They already have atherosclerotic disease in their coronaries. We think the evidence is pretty strong that if you already have plaques in your coronaries, you really to have a lower blood-pressure target. . . . Our IVUS data suggest that there is opportunity here to help patients."
Nissen admitted that the issue needs to be studied further and that the ongoing AQUARIUS study will assess changes in atherosclerotic disease progression with aliskiren (Tekturna, Novartis) when given in addition to standard therapy in CAD patients with prehypertension.
More data still needed
In an editorial accompanying the published study, Drs Jonathan Tobis and Alice Perlowski (University of California, Los Angeles) write that human and animal data make clear that a combination of aggressive lipid and blood-pressure control are necessary for a maximum attenuation of plaque progression, improved endothelial function, and reduced inflammation caused by oxidative stress [2].
Regarding the treatment of prehypertensive patients, Tobis and Perlowski write that a lack of data has contributed to a delayed acceptance of the need for drug therapy. In addition to AQUARIUS, the ongoing SPRINT, which is comparing intensive blood-pressure control (<120>130 mm Hg who have one additional risk factor, will help answer those questions.
The editorialists note that plaque progression/regression on IVUS is helpful in determining whether or not clinicians are helping their patients, but hard clinical end points are still needed, especially as they are shown to correspond with predictions based on the IVUS surrogates. Until then, "conclusions derived from these trials should be considered inferential, to be used as guides for future trials focused on clinical-outcomes measures," they write.
Asked about the polypill, Nissen told heartwire that he was not an initial fan, but with these and other data, he is starting to warm up to it. "The idea of having something that you go and get for $10 for three months that would control your blood pressure and your lipids, this study makes the case that it might make some sense."
New results about a polypill approach for primary prevention, combining a BP-lowering drug, a statin, and aspirin in a single pill, will be presented at the American College of Cardiology 2009 meeting next week.
| Nissen reports receiving research support from AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and Sanofi-Aventis and that he donates honoraria, consulting fees, and other payments directly to charity. Chhattriwalla reports no conflicts. |
- Chhatriwalla AK, Nicholls SJ, Wang TH, et al. Low levels of low-density lipoprotein cholesterol and blood pressure and progression of coronary atherosclerosis. J Am Coll Cardiol 2009; 53: 1110-1115.
- Tobis JM, Perlowski A. Atheroma volume by intravascular ultrasound as a surrogate for clinical endpoints. J Am Coll Cardiol 2009; 53: 1116-1118.
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