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A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events

Edwin J. Whitney, MD; Richard A. Krasuski, MD; Bradley E. Personius, MD; Joel E. Michalek, PhD; Ara M. Maranian, MD; Mark W. Kolasa, MD; Erik Monick, MD; B. Gregory Brown, MD, PhD; and Antonio M. Gotto Jr., MD, DPhil
[+] Article and Author Information

From Heart and Vascular Institute of San Antonio, San Antonio, Texas, Wilford Hall Medical Center, Lackland Air Force Base, and University of Texas School of Public Health, Houston, Texas; Cardiology Consultants, Grant Pass, Oregon; Northwestern University, Chicago, Illinois; University of Washington School of Medicine, Seattle, Washington; and Weill Medical College of Cornell University, New York, New York.


Disclaimer: The opinions expressed in this article are those of the authors, not the U.S. Air Force.

Acknowledgments: The authors thank Jennifer Palmer for her assistance with editing the manuscript.

Grant Support: By an unrestricted grant from the Parke Davis Branch of Pfizer Pharmaceuticals.

Potential Financial Conflicts of Interest: Consultancies: R.A. Krasuski (Pfizer Pharmaceuticals), A.M. Gotto Jr. (Pfizer Pharmaceuticals); Honoraria: R.A. Krasuski (Pfizer Pharmaceuticals), A.M. Gotto Jr. (Pfizer Pharmaceuticals, Kos Pharmaceuticals); Grants received: R.A. Krasuski (Pfizer Pharmaceuticals).

Requests for Single Reprints: Richard A. Krasuski, MD, U.S. Air Force Medical Center, 759 MSGS/MCCC, 2200 Bergquist Drive, Suite 1, Wilford Hall Medical Center, Lackland Air Force Base, TX; e-mail, Richard.krasuski@lackland.af.mil.

Current Author Addresses: Dr. Whitney: Heart and Vascular Institute of Texas, 1933 NE Loop 410, San Antonio, TX 78217.

Drs. Krasuski, Maranian, and Kolasa: 759 MSGS/MCCC, 2200 Bergquist Drive, Suite 1, Wilford Hall Medical Center, Lackland Air Force Base, TX 78236-5300.

Dr. Personius: Cardiology Consultants, 520 SW Ramsey Avenue, Suite 101, Grants Pass, OR 97526.

Dr. Michalek: University of Texas School of Public Health, 5323 Harry Hines Boulevard, V8.112M, Dallas, TX 75390-9128.

Dr. Monick: Department of Medicine, Northwestern University—The Feinberg School of Medicine, 251 East Huron Street, Galter Pavilion, Suite 3-150, Chicago, IL 60611.

Dr. Brown: Box 356422, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6422.

Dr. Gotto: Joan and Samuel Weill College of Medicine, Cornell University, 1300 New York Avenue, Box 5, New York, NY 10021.

Author Contributions: Conception and design: E.J. Whitney, B.G. Brown.

Analysis and interpretation of the data: E.J. Whitney, R.A. Krasuski, B.E. Personius, A.M. Maranian, M.W. Kolasa, E. Monick, B.G. Brown.

Drafting of the article: E.J. Whitney, R.A. Krasuski, B.E. Personius.

Critical revision of the article for important intellectual content: E.J. Whitney, R.A. Krasuski, B.E. Personius, A.M. Maranian, E. Monick, B.G. Brown, A.M. Gotto Jr.

Final approval of the article: E.J. Whitney, R.A. Krasuski, B.G. Brown, A.M. Gotto Jr.

Provision of study materials or patients: E.J. Whitney.

Statistical expertise: E.J. Whitney, R.A. Krasuski, J.E. Michalek.

Obtaining of funding: E.J. Whitney.

Administrative, technical, or logistic support: E.J. Whitney, R.A. Krasuski, A.M. Maranian.

Collection and assembly of data: E.J. Whitney, R.A. Krasuski, A.M. Maranian, M.W. Kolasa, E. Monick.


Ann Intern Med. 2005;142(2):95-104. doi:10.7326/0003-4819-142-2-200501180-00008
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The Armed Forces Regression Study demonstrates that a strategy aimed at increasing HDL cholesterol levels in patients with low baseline LDL cholesterol levels and established coronary disease arrests angiographic progression and might reduce the rate of some cardiovascular events. Furthermore, this strategy is beneficial when patients are already subjected to aggressive lifestyle modification. The latter strategy resulted in a significant loss of weight in the entire cohort and dramatically reduced overall cardiovascular risk. In fact, no patient experienced a myocardial infarction over the 30-month follow-up period, and only 1 death in the placebo group could be attributed to cardiovascular disease, even though all patients were considered high risk (documented, obstructive coronary artery disease) at the time of randomization. The timing of the study (initiated before the advent of statin mortality data and aggressive LDL cholesterol goals) permitted the observation of clinical effects with less confounding from the now well-established benefits of statins. The small sample size, powered toward an angiographic outcome, limits the ability to assess clinical outcomes. However, despite inclusion of so-called soft end points (transient ischemic attack and angina requiring hospitalization) in the composite clinical end point, we observed a tendency toward reduced need for revascularization with the combination drug therapy, thus reinforcing the relevance of the angiographic findings.

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Figure 2.
Kaplan–Meier event-free survival curves for patients in the control and treatment groups of the Armed Forces Regression Study.

Defined clinical events included hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, percutaneous intervention, coronary bypass, or death. The composite clinical end point decreased 52% after 30 months of follow-up (  = 0.039).

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HDL Elevation and Plaque Burden
Posted on January 20, 2005
Stephen J Nicholls
Cleveland Clinic Foundation
Conflict of Interest: None Declared

Whitney and colleagues (1) provide an interesting glimpse into the agents that elevate high-density lipoprotein (HDL) cholesterol levels in the pre- statin era. The combination of a fibrate, niacin and a bile-acid sequestrant increased plasma HDL levels by 37%. This was associated with a beneficial impact on atherosclerotic burden and a combination of clinical end points. Careful follow-up resulted in effective compliance with both dietary modification and consumption of pharmacologic agents that have traditionally been associated with high intolerability rates.

The reported effect on plaque burden should be interpreted with caution. Atherosclerotic extent was measured by coronary angiography, using a global estimate of severity and qualitative assessment. This result should be viewed in the context of previous reports that infusion of reconstituted HDL promoted rapid atherosclerotic regression, as assessed by intravascular ultrasound, a more accurate measure of plaque burden. (2) Further, when patients who did not proceed to follow-up angiography were included in the analysis it was assumed that there was no change in their plaque burden. This is in contrast to the stated assumption that standard medical care during this period would be associated with a 2% progression in angiographic stenosis. This assumption should be applied to the analysis.

It is premature to dismiss the concept that these agents had no impact on inflammation. While fibrinogen levels were not altered, CRP was not reported. It is likely that the beneficial effects of fibrate therapy results, in part, from the anti-inflammatory sequelae of their interaction with the PPAR-alpha receptor. (3)

Strategies to raise plasma HDL are of immense interest. It remains unclear whether its quantity or quality is more important. Ultimately, we need to consider that whatever therapeutic options are developed to promote HDL, they will need to be tested in the setting of statin therapy.

References

1. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, et al. A randomised trial of a strategy for increasing high-density lipoprotein cholesterol levels: Effects on progression of coronary heart disease and clinical events. Ann Intern Med. 2005;142:95-104.

2. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomised controlled trial. JAMA. 2003;290:2292-300.

3. Pineda Torra I, Gervois P and Staels B. Peroxisome proliferator- activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging. Curr Opin Lipidol. 1999;10:151-9.

Conflict of Interest:

None declared

Biochemical sequelae when increasing HDL levels
Posted on February 15, 2005
Viliam Lustig
The Research Institute at Lakeridge Health, Oshawa, Ontario, Canada
Conflict of Interest: None Declared

Whitney et al (1) report on a treatment regimen utilizing gemfibrozil, with staged introduction of niacin and cholestyramine, which was targeted to increase the HDL cholesterol in their study population, which had relatively normal LDL cholesterol levels (3.3 mmol/L on average). Their results show an improvement in the global angiographic stenosis in the study group, and they emphasize the association with a 36% increase in HDL cholesterol. However, the treatment regime had an effect on the overall plasma lipid profile. Concomitant with the rise in the HDL cholesterol there was also a decrease in total cholesterol (20%), LDL cholesterol (26%) and triglycerides (50%) which was to be expected from the known effects of these drugs. Whitney et al further indicate that there was a significantly greater increase in fasting glucose in their treatment arm "“ an average increase of 17.6%. This increase in the fasting glucose level leads us to believe that perhaps one in seven of the patients in the treatment arm might have developed pre-diabetes (fasting glucose 6.1-7.0 mmol/L), a condition which leads to an increased risk of Type 2 diabetes, heart attack and stroke. Indicating the number of patients (if any) who became pre-diabetic in the treatment group would facilitate a better understanding of the risk benefit ratio of their treatment. The article also reports incorrect fasting blood glucose concentrations in Table 1, when the concentration is reported in SI units (81 and 82 mg/dL is 4.5 mmol/L, not 2.1 mmol/L as reported). The biochemical profile at the 50-week follow-up showed a 36% increase in the HDL cholesterol level in the treatment arm. Since the lipid levels were measured at monthly intervals, it would be useful to report the time course of HDL improvements in the treatment group. Brousseau et al (2) recently reported a similar 46% increase in HDL cholesterol after only one month of treatment with torcetrapib (an inhibitor of cholesteryl ester transfer protein). Reporting the biochemical changes at earlier times in the Whitney et al study would facilitate the comparison of these two treatment strategies.

References:

1. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, et al. A randomized trial of a strategy for increasing high- density lipoprotein cholesterol levels: Effects on progression of coronary heart disease and clinical events. Ann Intern Med. 2005; 142: 95-104.

2. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004; 350: 1505-15.

Conflict of Interest:

None declared

The Authors Respond
Posted on March 21, 2005
Richard A. Krasuski
Wilford Hall Medical Center
Conflict of Interest: None Declared

We appreciate Dr. Nichols' comments and agree that the agents studied in the Armed Forces Regression Study (AFREGS), particularly niacin, have not traditionally been well tolerated. With newer formulations of niacin and proper patient instruction, much improved compliance has been achieved(1). Until newer agents have undergone more rigorous study and review, niacin remains the single most effective agent to raise high density lipoprotein cholesterol (HDL). Whether its well established clinical benefits are derived from changes in quantity or quality of HDL or low density lipoprotein cholesterol remains controversial, and unfortunately lipoprotein subtyping was not performed in the AFREGS population.

Though fibrinogen levels did not change with therapy, modulation of inflammation by study drugs cannot be excluded by such a small study. We examined fibrinogen and white blood cell count (WBC) in several subsets of patients in AFREGS and could not find evidence of any greater benefit in patients with increased inflammation, or evidence that levels of fibrinogen or WBC were significantly altered by therapy.

In terms of assessing atherosclerotic burden, we agree with Dr. Nichols that intravascular ultrasound (IVUS) is a tremendous advance and provides significantly better plaque characterization than angiography(2). It unfortunately remains slightly more invasive, is time consuming, and is not widely available. It is also important to note that despite the limits of angiography, the AFREGS results and the results of other quantitative coronary angiography studies do not dramatically differ in magnitude from recent studies using IVUS(3). In particular, in the REVERSAL study, a 1.4% difference in % obstructive volume was seen in comparing high and moderate dose statins(4). Using the suggested 2% progression of atherosclerosis in those patients not receiving final angiography in AFREGS, the difference in progression between treatment groups remains ~2% (0.6% reduction with combination therapy compared with a 1.5% progression in patients receiving placebo), with even stronger statistical significance.

The use of combination therapy without a statin, despite our favorable results, cannot be generally recommended for the secondary prevention of cardiovascular disease. The proven benefit for statins in the reduction of clinical events, including myocardial infarction, stroke, and death is too significant to totally disregard. Guidelines mainly recommend targeted HDL treatment if goal levels are not achieved with diet, lifestyle, and statins(5). For primary prevention, however, the data are less clear and further studies will be necessary to establish the most effective treatment strategy.

Richard A. Krasuski, M.D. Wilford Hall Medical Center San Antonio, TX

Edwin J. Whitney, M.D. Heart and Vascular Institute of Texas San Antonio, TX

1. Knopp RH. Evaluating niacin in its various forms. Am J Cardiol. 2000;86(12A):51L-56L. 2. Schoenhagen P, Nissen SE. Coronary atherosclerotic disease burden: an emerging endpoint in progression/regression studies using intravascular ultrasound. Curr Drug Targets Cardiovasc Haematol Disord. 2003;3(3):218- 26. 3. Thompson GR. Angiographic trials of lipid-lowering therapy: end of an era? Br Heart J. 1995;74(4):343-7. 4. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071-80. 5. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-421.

Conflict of Interest:

Consultant,Honoraria, and Grants received (Krasuski)

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Summary for Patients

Targeting Cholesterol Treatment toward Increasing High-Density Lipoprotein Levels

The summary below is from the full report titled “A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events.” It is in the 18 January 2005 issue of Annals of Internal Medicine (volume 142, pages 95-104). The authors are E.J. Whitney, R.A. Krasuski, B.E. Personius, J.E. Michalek, A.M. Maranian, M.W. Kolasa, E. Monick, B.G. Brown, and A.M. Gotto Jr.

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