Elena V Kuklina, MD, PhD, FACN Centers for Disease Control and Prevention, Atlanta, GA

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Disclaimer The opinions, findings, and conclusions in this

presentation are mine and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Es#mated  Number  of  US  Adult  with  Hypertension  and  High  Cholesterol  in  2005-­‐2008  (MMWR  Morb  Mortal  Wkly  Rep.  2011  Feb  4;60(4):109-­‐14)  

   Low-­‐density  lipoprotein  cholesterol  (LDL-­‐C)  and  cardiovascular  disease  (CVD)  risk  reduc#on  

Coronary  heart  disease  

Stroke  

Es#mated  benefits  of  lowing  LDL-­‐C  by  1  mmol  (39  mg/dL)  using  sta#ns  in  adults    (Lancet.  2012  Aug  11;380(9841):581-­‐90)    

Outcomes   Magnitude  of  risk  reduction,  %  

Point  estimate  

95%  confidence  intervals  

Major  coronary  event   24    21-­‐27  

Any  stroke   15     11-­‐20  

Major  vascular  event   21   19-­‐23  

Vascular  mortality   12    9-­‐16  

Major  vascular  events:  major  coronary  event  (non-­‐fatal  myocardial  infarction  or  coronary  death),  any  stroke,  and  coronary  revascularizations  

 NCEP,  ATP-­‐III:  Example  of  Risk  Categories  and  LDL-­‐C  goals  Risk  of  CHD  during  the  next  10  years    

Conditions  and  risk  factors  

LDL-­‐C  goal  (mg/dL)  

High  (>20%)   Coronary  heart  disease  (CHD),  non-­‐coronary  atherosclerosis,  diabetes  

<100  

Intermediate  (10-­‐20%)  

Multiple  (2+)  risk  factors*   <130  

Low  (<10%)  

0-­‐1  risk  factors   <160  

Define  risk  

#RF  

<2  

Low  risk  

2+  

Calculate  Framingham  

score  

CHD  or  equivalent  

High  risk  

Major  Risk  Factors  (Exclusive  of  LDL    Cholesterol)  That  Modify  LDL  Goals  � Cigarette  smoking  � Hypertension  (BP  ≥140/90  mmHg  or  on    antihypertensive  medication)  

� Low  HDL  cholesterol  (<40  mg/dL)†    � Family  history  of  premature  CHD  

� CHD  in  male  first  degree  relative  <55  years  � CHD  in  female  first  degree  relative  <65  years  

� Age  (men  ≥45  years;  women  ≥55  years)  † HDL cholesterol ≥60 mg/dL counts as a “negative” risk factor; its

presence removes one risk factor from the total count.

Define  risk  

#RF  

<2  

Low  risk  

2+  

Calculate  Framingham  

score  

CHD  or  equivalent  

High  risk  

Framingham  Risk  Factors  (calculated  for  men  and  women  separately)  � Age  � Cigarette  smoking  � Systolic  blood  pressure,  mm  Hg  (treated  and  untreated)  

� High  Density  Lipoprotein  cholesterol,  mg/dL    

� Total  cholesterol,  mg/dL  

Did  you  know?     �  2011    

�  nearly  20  million  Americans  regularly  used  lipid  regulators  

   �  dispensed  prescriptions  for  statins  exceeded  260  million  

�  63%  filled  with  a  generic  drug  (vs.  78%  for  all  medications)    

�  The  most  prescribed  generic  statin  is  #2  prescribed  medication  -­‐-­‐  94.1  million  prescriptions  

Clinical  Quality  Measures  (CQM)  for  Lipid  Management  by  Na#onal  Quality  Forum  (NQF)  

*a  minimum  the  prescription  of  a  statin  

Indicator   Population  with   Specification  Ischemic  Vascular  Disease  (IVD)  :  lipid  profile  and  control  NQF  0075)  

%  of  patients  discharged  alive  for  IVD  (18+  years)  

•  Complete  Lipid  Profile  •  LDL-­‐C  l  <100  mg/dL  

Coronary  Artery  Disease  (CAD):  control  and  drug  therapy    (NQF  0074)  

%of  patients  with  a  diagnosis  of  CAD  (18+  years)  

LDL-­‐C  <100  mg/dL  OR    documented  plan  of  care  to  achieve  LDL-­‐C  <100mg/dL*  

Diabetes  Mellitus:  control    (NQF  0064)  

%  of  patients  with  diabetes  (18-­‐75  years)  

LDL-­‐C  <100  mg/dL    

The  bo\om-­‐line?  

� Reliable  and  accurate  determination  of  LDL-­‐C  concentration  is  mandatory  

Two  components  of  analy#cal  laboratory  error    

Inaccuracy  (bias)  

 

Imprecision  (coefficient  of  variation)  

 

Objec#ves  of  the  study    

At  population  level,  investigate  implication  of  analytical  bias    for  HDL-­‐C,  TC,  and  LDL-­‐C  measurements  on  

1.   Coronary  Heart  Disease  risk  group  misclassification  

2.   Under-­‐  and  overtreatment  

Na:onal  Health  and  Nutri:on  Examina:on  Survey  (NHANES)  �  Continuous  data  collection,  released  as  2-­‐year  data  

�  Annual  national  sample  of  6,000-­‐7,000  persons  

�  Civilian,  non-­‐institutionalized  population  �  Complex,  multistage  probability  design  �  204,936,643  (N=2,266)  adults  20  years  and  older  

�  Exclusions:  pregnant  women  and  missing  data  

 College  of  American  Pathologists  (CAP)    

� Accuracy-­‐based  Lipids  Survey  (ABL)  

�  140-­‐190  laboratories  � N=3,625  � Lipid  profile  

 College  of  American  Pathologists  (CAP)    

� 25%  percentiles  (positive)  

 � LDL-­‐C=+7.8%  � TC=+1.6%  � HDL-­‐C=+2.3%  

� 75%  percentile  (negative)  

� LDL-­‐C=-­‐1.2%  � TC=-­‐1.3%  � HDL-­‐C=-­‐6.8%  

Examples  of  misclassifica4ons  

Reference   Bias  

HDL   Risk  score   Risk  group   HDL   Risk  score   Risk  group  

39   0   low   36  (-­‐)   +1   medium  

39   0   low   42  (+)   0   low  

63   0   medium   59  (-­‐)   -­‐1   low  

63   0   medium   67  (+)   0   medium  

all   20-­‐44  years   45-­‐64  years   65+  years  high   97.5   95.5   96.4   98.6  medium     92.6   88.4   94.3   92.5  low   100   100   100   100  

0  10  20  30  40  50  60  70  80  90  100  

Per

cent

 Positive  bias  (25%th  percentile):  Percent  of  correctly  risk  classified  adults  aged  20  years  and  older,  NHANES,  2007-­‐2008  

all   20-­‐44  years   45-­‐64  years   65+  years  high   99.6   100   99.1   100  medium     98   100   97.6   95.7  low   94.4   97.2   92.3   85.5  

0  10  20  30  40  50  60  70  80  90  100  

Per

cent

 Negative  bias  (75%th  percentile):  Percent  of  correctly  risk  classified  adultes  aged  20  years  and  older,  NHANES,  2007-­‐2008  

all   20-­‐44  years   45-­‐64  years   65+  years  Negative   6.4   11.4   4.9   3.6  Positive   0.3   0.7   0.2   0.3  

0  

2  

4  

6  

8  

10  

12  

Per

cent

 Percentage  of  potentially  undertreated  adults  20  years  and  older,  NHANES  2007-­‐2008  

all   20-­‐39  years   40-­‐60  years   60+  years  Positive   9.1   5.6   14.3   14  Negative   1.8   0.7   2.8   5.6  

0  

2  

4  

6  

8  

10  

12  

14  

16  

Per

cent

 Percentage  of  potentially  overtreated  adults  20  years  and  older,  NHANES  2007-­‐2008  

Conclusions  �  Analy#cal  bias  has  dis#nc#ve  implica#ons  on  CHD  risk  and  treatment  misclassifica#ons  by  age    

�  Compared  to  old  adults,  young  adults    �  are  more  likely  to  be  undertreated  if  their  lipid  profile  was  assessed  in  laboratory  with  substan#al  nega#ve  bias  (N=  1,142,749)  

�  Compared  to  young  adults,  middle-­‐age  and  old  adults    �  are  more  likely  to  be  overtreated    if  their  lipid  profile  was  assessed  in  laboratory  with  both  substan#al  posi#ve  bias  (N=5,899,514  and  N=1,959,016)  

The  truth  about  Friedewald  equa4on  

�  the  “Friedewald  formula”  using  measured  values  for  total  cholesterol,  HDL-­‐C,  and  triglyceride:    

 

�  LDL-­‐C  =  (TC)  -­‐  (HDL-­‐C)  -­‐  (TG/5);  where  units  are  mg/dL    

What  the  NHANES  analy#c  guidelines  do  not  tell  you?  

•  Non-­‐fasting  •  Complete  automation  •  Poor  agreement  with  reference  methods  •  Significant  method-­‐specific  bias  •  Have  not  been  adequately  standardized  

Direct  LDL-­‐C    

•  Fasting  •  Underestimation  of  LDL-­‐C    •  TG  levels≥150  mg/dl  •  HDL-­‐C  (dHDL-­‐C)  methods  •  Conditions:  diabetes,  known  vascular  disease,  hepatic  failure,  lipid-­‐lowering  medications,  etc.  

Calculated  

Acknowledgments  

� Hubert  Vesper  � Kate  Shaw  � Rob  Merritt  �  Fleetwood  Loustalot  � Yuling  Hong  � Barbara  Bowman