Primecuts – This Week In the Journals

November 21, 2011

By Juliette Provenzano-Gober, MD

Faculty Peer Reviewed

The FDA announced this week that they are revoking Avastin (bevacizumab) approval for treatment of metastatic HER 2 negative breast cancer. The FDA commissioner, Margaret A. Hamburg, MD, concluded that Avastin has serious side effects such as elevated blood pressure and hemorrhage without proof that it will provide benefit. [12] Hypertension can lead to further cardiovascular complications and with questionable oncological benefit, this drug will no longer be recommended for patients with breast cancer. This brings us to cardiovascular health in general, which appeared to be the theme this week in some of our favorite journals. In light of last week’s Primecuts where it was discussed that the Academy of Pediatrics has made a recommendation of screening children for cholesterol and diabetes at the age of 9 and up, focusing on cardiovascular data is quite fitting for this week’s Primecuts. [1] Ok, well let’s get to the crux of this data.

First, the Journal of the American Medical Association highlights a riveting randomized control trial examining the effects of cholesteryl ester transfer (CETP) inhibitors as cardioprotective agents. There had previously been some hype surrounding a previous CETP inhibitor, Torcetrapib, in 2007. During this trial, treatment with Torcetrapib resulted in increased mortality and morbidity as a result of elevated blood pressures and aldosterone levels and the trial was prematurely halted. [2] There was, however, some evidence that the toxicity associated with this drug is off-target and suggests another compound of the same class may be effective with a limited side-effect profile. [3] In this new study, Evacetrapib is evaluated in patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C). At baseline the patient population had a mean LDL-C of 144.3 mg/dL, HDL-C of 55.1 mg/dL and triglycerides of 121.3 mg/dL. Patients were excluded if they had atherosclerotic disease, hypertension, hyperaldosteronism, or uncontrolled diabetes. A total of 398 patient were randomized to placebo, Evacetrapib monotherapy or statin therapy with or without Evacetrapib. The primary end points were percent changes in LDL-C and HDL-C after 12 weeks of treatment. The results were quite encouraging. Evacetrapib monotherapy had dose-dependent increases in HDL-C ranging from 54-129% in comparison with placebo and decreases in LDL-C of 14 to 36% compared with the placebo. When administered with the statin therapy, Evacetrapib increased HDL-C levels 79-89% compared with statin alone and resulted in greater reductions in LDL-C in comparison to monotherapy with statin. Apolipoprotein A-1, A-2 and E dose-dependent increases were also found in comparison with the placebo. No significant increases in blood pressure or aldosterone as found in the prior study were found. It looks like Evacetrapib may be a promising adjunct to the already popular statins in further reducing LDL and raising HDL. [4]

Let’s move onto those already infamous statins, a staple in our medical toolbox since 1987 for patients with hyperlipidemia, coronary artery disease, and cardiac risk factors. The SATURN trial, The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin, was a prospective, randomized, multi-center double blinded trial, which sought to determine if two well-known statins at maximum dosages would have evident differences in their effects on progression of coronary atherosclerosis. The primary end point was atheroma volume (PAV) and the secondary end point was total atheroma volume (TAV). 1385 patients were assigned to full dose treatment with atorvastatin or rosuvastatin after having baseline imaging performed via intravascular ultrasound. After 104 weeks, patients were reimaged and PAV decreased by 0.99% in atorvastatin group and 1.22% in rosuvastatin group and TAV showed a reduction of 6.39 mm in the atorvastatin group vs. 4.42 mm in the rosuvastatin group. During the 104 weeks of observation, the mean LDL levels were 70 mg/dL in the atorvastatin group and 62 mg/dL in the rosuvastatin group demonstrating effectiveness of both drugs on lipid lowering, more-so in the rosuvastatin group. Despite the effectiveness as demonstrated on laboratory data, there was not a significant effect on disease regression as implied by the primary end point, although there was a relatively small benefit with respect to rosuvastatin in terms of the secondary end point. [5]

Another article in this week’s NEJM that may rock your world is the AIM-HIGH study, which showed that despite increases in HDL, an independent risk factor for coronary heart disease, niacin does not have any clinical benefit when added to statins. [6] This study was an investigator-initiated randomized control trial. Eligible patients were 45 years old or older and had known cardiovascular disease; all had low HDL and elevated triglyceride levels, and LDL levels less than 180 if not already on a statin. Patients were randomized to niacin (dose 1500-2000 mg per day) plus simvastatin or placebo (containing 50 mg niacin) plus simvastatin. The composite primary end point was death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization, or symptom-driven coronary or cerebral revascularization. At two years, HDL cholesterol increased by 25% in the niacin group and increased by 10% in the placebo group, triglycerides decreased by 29% in the niacin group and 8 in the placebo group, the LDL cholesterol decreased by 12% in the niacin group and 6 in the placebo group. Despite such encouraging laboratory findings, the authors did not find a significant difference in rate of primary end point with 16% in both the niacin and placebo group. In addition, there was an increased rate of ischemic stroke in the niacin group whose significance is still unclear, causing the study to be halted prematurely at 3 years. This data is in stark comparison to earlier trials suggesting decreased cardiovascular events associated with niacin use. [8,9] This may make us rethink adding niacin to our patient’s regimens when they are maxed out on statins.

Now that we have exhausted one of the major risk factors associated with coronary heart disease, let’s focus on a study that sought to examine the association between cardiac risk factors and hospital mortality in first myocardial infarction. This meta-analysis gathered data from The National Registry of Myocardial Infarction. The five risk factors analyzed included hypertension, smoking, dyslipidemia, diabetes and family history of coronary heart disease. The outcome was all-cause mortality. The results are as follows. There was an inverse relationship between the number of coronary risk factors and median age. The most common risk factor with patients presenting with initial MI was hypertension (52%), followed by smoking (31%). There was a direct association between obesity and increasing number of risk factors. Counter-intuitively, there was an inverse relationship between the number of risk factors and the severity of illness upon presentation, with the highest proportion of patients having cardiogenic shock having no risk factors. These patients also had a lower ejection fraction, more cardiac rupture, shock and arrhythmias. In terms of the primary end point, there was an inverse relationship between all-cause mortality and risk factors: no risk factors-15%, one risk factor-11%, two risk factors-8%, three risk factors 5%, four risk factors-4% and five risk factors-4%. [10]

Finally, The New England Journal of Medicine brings us back to our childhood, where it examines childhood obesity and its implications for increased cardiac risk. Juonala et al. sought to determine if an obese child will have the same risk factors whether they remain obese or become non-obese as an adult. This would help determine if nutrition and weight loss education in childhood and teenage years could prevent later cardiovascular disease. The authors examined four cohorts from large trials following subjects from childhood to adulthood and analyzing development of cardiovascular risk factors including diabetes, dyslipidemia, hypertension and carotid artery atherosclerosis. In the pooled analyses, there were associations between being overweight and obesity as a child and the development of the four high-risk outcomes. The risks among the subjects who were overweight or obese in childhood but not as an adult were similar to those subjects who had consistently normal BMIs. Subjects who were obese as adults regardless of their childhood weight had an increased risk or outcome. [11]

Let it be known that several of these studies are “online first” as they were presented last week in Minnie and Mickey’s hometown, Orlando, Florida, at the American Heart Association Scientific Sessions. Therefore, don’t expect to find them in your old-fashioned mailbox.

Dr. Juliette Provenzano-Gober is a 2nd year resident at NYU Langone Medical Center

Peer Reviewed by Barbara Porter, Section Editor, Clinical Correlations

References:

1. Kavey RE et al. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 128:5. December 2011. Available at: http://pediatrics.aappublications.org/site/misc/2009-2107.pdf.

2. Barter P et al. Effects of Torcetrapib in patient at high risk for coronary events. NEJM. 2007;357(21):2109-2122. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0706628

3. Vergerr M. et al. The pharmacology and off-target effects of some cholesterol ester transfer protein inhibitors. Am J Cardiology. 2009;104(10)(suppl):32E-38E. Available at: http://www.ajconline.org/article/S0002-9149(09)02378-9/abstract

4. Nicholls S. et al. Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol. JAMA. 2011;306(19):2099-2109. Available at: http://jama.ama-assn.org/content/306/19/2099.full

5. Nicholls S. et al. Effects of Two Intensive Statin Regimens on Progression of Coronary Disease. NEJM. 10.1056. 11/15/11. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1110874?query=featured_home

6. Castelli WP et al. Cholesterol and lipids in the risk of coronary artery disease—The Framingham Heart Study. Can J Cardiol. 1988;4:suppl:5A-10A. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3179802

7. Boden W. et al. Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. NEJM. 10.1056. 11/15/11. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1107579

8. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975; 231:360-81. Available at: http://jama.ama-assn.org/content/231/4/360.extract

9. Rubens HB et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. NEJM 1999;341:410-8. Available at: http://www.nejm.org/doi/full/10.1056/NEJM199908053410604?hits=20&andorexactfulltext=and&where=fulltext&searchterm=The+VA+HDL+intervention+trial%3A++Gemfibrozil+for+the+secondary+prevention+of+coronary+heart+disease+in+men+with+low+HDL-cholesterol&sortspec=S

10. Canto J. et al. Number of Coronary Heart Disease Risk Factors and Mortality in Patients with First Myocardial Infarction. JAMA 2011;306(19):2120-2127. Available at: http://jama.ama-assn.org/content/306/19/2120

11. Juonala M. et al. Childhood Adiposity, Adult adiposity and Cardiovascular Risk Factors. NEJM 2011;365(20):1876-1885. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0904130

12. Margaret A. Hamburg. FDA Commissioner announces Avastin decision. US Food and Drug Administration. 11/18/11. Internet. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280536.htm

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