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April 2008 in Review

• Measurement of coronary artery calcification on non contrast cardiac CT predicts CHD events above and beyond Framingham risk score in a multi-ethnic cohort.
• A high proportion of individuals with metabolic syndrome are considered as “low risk” by Framingham risk score based NCEP guidelines.
• Aggressive lipid and blood pressure lowering results in regression of carotid artery atherosclerosis in diabetics.
• Addition of ezetimibe to statin does not result in lowering subclinical atherosclerosis burden.
• Presence of CAC is associated with increased utilization of preventive cardiovascular medication.
• Asymptomatic individuals with high coronary artery calcium scores more likely to improve lifestyle behavior and increase preventive medication use.
• Combination of coronary artery calcification and assessment of myocardial perfusion defects identifies high risk individuals better than either alone.
• Assessment of vascular functions significantly improves CHD risk stratification in post-menopausal women.
• Antihypertensive vaccination found to be safe, tolerated and effective in short term follow-up.
• Medication non-adherence in high risk patients associated with severe CVD outcomes.
   

Measurement of coronary artery calcification on non-contrast cardiac CT predicts CHD events above and beyond Framingham risk score in a multi-ethnic cohort.

Detrano R et al; N Engl J Med. 2008 Mar 27;358(13):1336-45

Aim

To evaluate whether coronary-artery calcium (CAC) screening predicts coronary heart disease in a multi-ethnic asymptomatic population above and beyond than those with Framingham risk score (FRS).

Methods

• The study population consisted of 6722 men and women (39% white, 27% were black, 22% were Hispanic, and 12% were Chinese).
• All known cardiac risk factors as 10 year risk of cardiac event based on FRS were assessed in all of these individuals.
• A non contrast cardiac CT was performed to assess underlying presence as well burden of CAC.
• The primary outcome in this study was any as well hard coronary heart disease (CHD) events.
  
  

Results

• The study population was followed for a median of 3.8 years.
• Overall 162 coronary events were recorded in the follow-up period, of which 89 were major events (myocardial infarction or death from coronary heart disease).
• As compared to those with CAC=0, the adjusted risk of a coronary event was 7.7 fold higher among those with CACS of 101 and 300; the respective risk increased by a factor of 9.67 among participants with CAC>300.
• Similar results were seen in all ethnic groups.
• On ROC curve analyses the area under the curve for FRS alone vs CAC scores+FRS was 0.79 and 0.83 respectively.

 SHAPE Perspective

• This study confirms finding of previous studies that the predictive value of CAC in identifying high risk individuals vulnerable to future CHD events.
• These findings provide compelling evidence for utilization of CACS in primary preventive CHD strategies in appropriate population. 
  
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A high proportion of individuals with metabolic syndrome are considered as “low risk” by Framingham risk score based NCEP guidelines

Hoang KC et al; Diabetes Care. 2008 Apr 4 [Epub ahead of print]

Aim

Determine the underlying global risk burden as determined by current CHD risk stratification tools.

Methods

• The study population consisted of 4293 U.S. adults aged 20-79 in the U.S. National Health and Nutrition Examination Survey (NHANES) 2003-2004.
• Metabolic syndrome (MS) was defined according to modified National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP III).
• The global risk categories were defined as follows; low, moderate, moderately high, and high risk status were defined as <6%, 6-10%, 10-20%, and >20% probability of CHD in 10 years (based on NCEP/ATP III Framingham risk score algorithms), respectively; those with diabetes or pre-existing cardiovascular disease were assigned to high risk status.
  
  

Results

• The overall weighted prevalence of MS in the NHANES population was in 29%
• More than one-thirds of those with MS were considered low risk (39%); more women compared to men were classified in this category (47% vs. 31%)
• On the other hand one thirds of them (37%) were considered high risk; no differences according to gender were observed (women: 37%, men: 38%)
• The rest of individuals with MS were classified as moderate to moderately high risk.
  
  

SHAPE Perspective

• A significant proportion of those with high underlying metabolic syndrome are considered ‘low-risk’ and thus less likely to achieve criteria for pharmacotherapy.
• The underestimation appeared more prominent in women, as also seen in previous studies.
• Measurement of underlying atherosclerotic burden and/or vascular function may appropriately identify those at higher risk for better identification of high risk individuals requiring aggressive preventive therapies. 
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Aggressive lipid and blood pressure lowering results in regression of carotid artery atherosclerosis in diabetics

Howard BV et al: ; JAMA. 2008 Apr 9;299(14):1718-20.

Aim

Evaluate changes in carotid intimal medical thickness (CIMT) in individuals with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of ≤70 mg/dL and systolic blood pressure (SBP) of ≤115 mm Hg or lower vs. standard targets of ≤LDL-C of 100 mg/dL and SBP of ≤130 mm Hg

Methods

• Study population consisted of 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events.
• Patients were randomized to aggressive (n=252) vs. standard (n=247) treatment groups.
• Primary end point was progression of atherosclerosis measured by CIMT. Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events.
  
  

Results

• Mean target LDL-C and SBP levels for both groups were reached and maintained over 12 months
• In the aggressive treatment group, C IMT regressed and progressed in the standard group (-0.012 mm vs. 0.038 mm; P < .001).
• In addition, there was greater decrease in left ventricular mass index (-2.4 g/m (2.7) vs. -1.2 g/m (2.7); P = .03) in the aggressive group.
• No change in rate of cardiac adverse events were seen in both groups
  
  

SHAPE Perspective

• The study finding implies that there are increased reduction in atherosclerosis burden can be achieved by treating diabetics to even lower LDL and SBP goals.
• Whether these changes will translate in improved CVD outcomes will be need to be assessed in longer term follow-up. 
  
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Addition of ezetimibe to statin does not result in lowering subclinical atherosclerosis burden

Kastelein JJ et al; N Engl J Med. 2008 Apr 3;358(14):1431-43

Aim

To assess the effect of combination of Ezetimibe (cholesterol-absorption inhibitor) combined with statin vs. statin alone on the progression of atherosclerosis

Methods

• The study population consisted of 720 patients with familial hypercholesterolemia.
• These patients were randomized to daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe.
• The primary outcome measure was the change in the mean carotid-artery intima-media thickness (CIMT) as marker of underlying subclinical atherosclerotic burden.
  
  

Results

• The trial was continued for 24-month.
• In the combined therapy group vs. simvastatin group a higher reduction in LDL and C reactive protein was observed.
• However no difference in the primary outcome (change in the CIMT) thickness, was observed in the simvastatin-only group vs. simvastatin-plus-ezetimibe (0.0058±0.0037 mm vs. 0.0111±0.0038 mm p=0.29)
• No differences in side-effect and safety profiles between the groups were detected.
  
  

 SHAPE Perspective

• Interestingly in spite of significant reduction in LDL and CRP, no differences in reduction in CIMT, a surrogate marker for atherosclerosis, was observed with additional use of ezetimibe was seen in this high profile trial.
• Whether this lack of change in CIMT will also translate in no benefit in reducing adverse CVD need to be determined in outcomes studies. 
  
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Presence of CAC is associated with increased utilization of preventive cardiovascular medication

Taylor AJ et al; J Am Coll Cardiol 2008 Apr 8;51(14):1337-41.

Aim

Assess the relationship of presence of coronary artery calcium (CAC) detected with statin and aspirin utilization in a healthy male cohort free of known cardiovascular disease.

Methods

• The study population consisted of 1,640 men (ages 40 to 50 years) who screening for coronary heart disease risk factors as well non-cardiac CT for presence of CAC.
• The CAC scores and risk factors were reported to patients with any prescription or recommendation of medication use in this study.
• The final study endpoint of the study was initiation and persistence of aspirin and statin therapy during a 6 year old prospective follow-up study.
  
  

Results

• During the 6 year follow-up those with CAC were 3 times more likely to receive a statin (48.5% vs. 15.5%, p < 0.001)
• In a similar fashion the utilization of aspirin was also high among those with CAC vs. CAC=0 (53.0% vs. 32.3%; p < 0.001) than those without CAC.
• After taking CHD risk factors into account, presence of CAC was strongly associated with use of statin (odds ratio: 3.53; 95% CI: 2.66 to 4.69) as well aspirin (OR 3.05; 95% CI 2.30 to 4.05).
• However on significant relationship was found with persistence of medication, which remained high irrespective of baseline CAC
  
  

SHAPE Perspective

• Presence of CAC not only predicts increased CHD risk and potential candidates requiring more aggressive treatment, but also is associated with at-least 3 fold increase in use of preventive medications such as statins and aspirin.
• This study is among the emerging evidence providing support that CAC screening can potentially improve CVD outcome in high risk vulnerable populations. 
  
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Asymptomatic Individuals with high coronary artery calcium scores more likely to improve lifestyle behavior and increase preventive medication use.

Orakzai RH  et al; Am J Cardiol. 2008 Apr 1; 101(7):999-1002

Aim

Assess whether higher coronary artery calcium (CAC) scores are associated with beneficial lifestyle behaviors in asymptomatic individuals

Methods

• The study population consisted of 980 (78% men, mean age 60 ± 8 years) asymptomatic individuals who underwent CAC testing for cardiovascular risk stratification.
• After a period of mean 3±2 years, a survey questioning them about health behaviors was send to these patients.
• The primary endpoint of this study was assessment of long term aspirin (ASA) utilization, changes in exercises and dietary behaviors.
  
  

Results

• Among those with CACS=0, during the 3 year follow-up, ASA initiation was lowest (29%) among those with CAC = 0, and increased with higher CAC scores (1 to 99, 55%; 100 to 399, 61%; ≥400, 63%; p <0.001 for trend).
• In a similar fashion, dietary changes and exercise improvements were lowest (33% and 44%, respectively) among those with CAC = 0 and gradually increased with higher CAC scores (1 to 99, 40%; 100 to 399, 58%; ≥400, 56%; p <0.001 for trend for dietary changes; and 1 to 99, 62%; 100 to 399, 63%; ≥400, 67%; p <0.001 for trend for exercise).
• In risk factors adjusted analysis those with CAC>400 vs. CAC=0, were 2-3 fold more likely to initiate ASA as well make beneficial dietary and exercise changes.
  
  

SHAPE Perspective

• In conclusion, in addition to risk stratification of asymptomatic individuals, determination of CAC may also improve utilization of ASA therapy and behavioral modification.
• Future studies are needed to elucidate whether these beneficial health related changes observed among those with higher coronary atherosclerotic burden will translate into improved outcomes in these high risk asymptomatic individuals. 
  
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Combination of coronary artery calcification and assessment of myocardial perfusion defects identifies high risk individuals better than either alone.

Schenker MP et al; Circulation. 2008 Apr 1; 117(13):1693-700

Aim

Compare the value of coronary artery calcium (CAC) and myocardial perfusion in prediction of CHD events in high risk individuals.

Methods

• The study population consisted of 695 consecutive patients (mean age 61.3±13.1 years, 41% male) who underwent combined rest-stress rubidium 82 PET perfusion imaging and CAC scoring on a hybrid PET-CT scanner.
• The primary outcome in this study was occurrence of serious clinical outcomes (death or MI) by review of the electronic longitudinal medical records at our institution and in the Social Security Death Index. 
  
  

Results

• The mean follow-up duration of the study was 524±212 days (maximum 866 days, minimum 15 days, median 553 days).
• A total of 55 cardiovascular events were observed (33 deaths and 22 nonfatal MIs).
• The sensitivity, specificity and negative predictive value for prediction of CVD event with CAC was 80%, 37% and 95%.
• The respective values for perfusion abnormalities were 49%, 75% and 94%.
• Overall 4% were seen in those without CAC and normal perfusion, whereas 9% and 8% events were observed in those with either perfusion abnormality or presence of CAC.
• Among patients with both presence of CAC as well ischemia, the event rate was 18%.
  
  

SHAPE Perspective

• The study provide further evidence to the notion that detection of structural as well physiological abnormalities add more prognostic information than either alone.
• However whether these results are generalize-able to low-intermediate risk populations cannot be determined from this study. 
  
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Assessment of vascular functions significantly improves CHD risk stratification in post-menopausal women.

Rossi R et al;  J Am Coll Cardiol. 2008 Mar 11;51(10):997-1002

Aim

Examine the utility of vascular function as measured by brachial artery flow-mediated dilation (FMD) and cardiovascular events in an asymptomatic cohort of initially asymptomatic post-menopausal women

Methods

• The study population consisted of a cohort on 2,264 post-menopausal women (mean age 54±6 years)
• Endothelial function was evaluated through the measure of the FMD performed on the brachial artery.
• The primary outcomes of the study were cardiac-related death, myocardial infarction, and 3, revascularization procedure (catheter-based or surgically), TIA, and stroke.

Results

• The study participants were followed for 45 ± 13 months (range 6 to 65 months).
• During the follow-up period, 91 events were reported.
• As compared to those with FMD in the highest levels (3^rd tertile), the hazard ratio for any cardiac event was 3.87 (95% CI: 2.05-8.55) and 6.36 (4.26-11.50) for women with FMD in the intermediate (2^nd tertile) and lowest level (1^st tertile) respectively.
• In multivariate analyses adjusting for age, gender and CVD risk factors those with CAC≥400 were nearly 3 times more likely to initiate ASA treatment compared to those CAC=0 (OR: 2.98, 95% CI: 1.83-4.83, p<0.001).

SHAPE Perspective

Vascular function measurements such as FMD may improve further risk stratification in asymptomatic high risk individuals and adds prognostic information above and beyond traditional risk factors.

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Antihypertensive vaccination found to be safe, tolerated and effective in short term follow-up.

Tissot AC et al; Lancet. 2008 Mar 8;371(9615):821-7

Aim

Determine the safety, tolerability as well effectiveness of a novel anti-hypertensive vaccine.

Methods

• The vaccine studied was CYT006-AngQb-which is based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure.
• The study was a multicentre, double-blind, randomized, placebo-controlled phase IIa trial.
• The study population consisted of 72 patients with mild-to-moderate hypertension who were randomly assigned to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12.
• The 24-h ambulatory blood pressure was measured before treatment and at week 14.
  
  

Results

• In the 300 mug group vs. placebo a reduced baseline in mean ambulatory daytime blood pressure at week 14 was observed (-9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic).
• In addition the 300 mug dose also reduced the early morning blood-pressure surge compared with placebo (-25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic).
• Overall no differences in adverse effect and tolerability were noted among the groups.

SHAPE Perspective

• The current study reports a new strategy to treat hypertension which appears to be safe, effective in short term follow-up.
• Although very encouraging, long term follow-up data especially after repeat stimulation should be sought to address safety and efficacy concerns.
  
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Medication non-adherence in high risk patients associated with severe CVD outcomes

Ho PM et al et al; Am Heart J. 2008 Apr;155(4):772-9

Aim

Determine the association between medication adherence and CVD outcomes among patients with known CAD.

Methods

• The study assessed retrospectively a cohort of patients in a large managed care organization registry with prior myocardial infarction, PCI, or CABG surgery.
• Medication adherence was calculated as the proportion of days covered (PDC), based on the total number of days supplied for each class of medication (i.e., β-blockers, ACE inhibitors, or angiotensin receptor blockers and statin medications) per observation time interval.
• The primary outcomes of the study were all-cause and cardiovascular mortality.
  
  

Results

• In adjusted multivariable analysis, the association between non-adherence and all-cause mortality was significantly higher; β-blocker (HR 1.50, 95% CI 1.33-1.71), ACE inhibitor (HR 1.74; 95% CI 1.52-1.98), and statin (HR 1.85, 95% CI 1.63-2.09)
• Similar findings for non-adherence and increased risk for cardiovascular mortality was seen for β-blocker (HR 1.53, 95% CI 1.16-2.01), ACE inhibitor (HR 1.66, 95% CI 1.26-2.60), and statin (HR 1.62, 95% CI 1.24-2.13) medications.
  
  

SHAPE Perspective

• Non-adherence to CVD medications is high in both primary and secondary preventive settings.
• There is an urgent need to identify the factors associated with non-adherence as well efforts should be initiated to utilize novel methods to improve adherence rates in these vulnerable populations. 
  
  
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