JGIM

CLINICAL REVIEW Cholesterol in Patients with Coronary Heart Disease: How Low Should We Go? Hanna Bloomfield Rubins, MD, MPH

CLINICAL P R O B L E M : To e x a m i n e the e v i d e n c e supporting

the recent National Cholesterol E d u c a t i o n Program (NCEP) r e c o m m e n d a t i o n that low to moderate levels of c h o l e s t e r o l should be aggressively m a n a g e d in patients w i t h coronary heart disease (CHD). M E T H O D S : Cohort s t u d i e s and clinical trials w i t h angio-

graphic or clinical endpoints, that included CHD patients w i t h low to moderate levels of c h o l e s t e r o l , were s y s t e m a t i c a l l y identified through a MEDLINE s e a r c h and critically reviewed. S Y N O P S I S . N o n e of the cohort s t u d i e s s h o w that a moderate

level of cholesterol confers significantly increased risk of CHD death, a l t h o u g h a p o o l e d relative risk o f 1 . 1 4 (95% CI 1 . 0 8 to 1.4) suggests that there m a y be a slight e x c e s s risk. Of five angiographic trials o f CHD patients w i t h moderate levels o f cholesterol, two d e m o n s t r a t e d n o i m p r o v e m e n t in angiographic e n d p o i n t s w i t h i n t e n s i v e lipid-lowering therapy and the other three are difficult to interpret s i n c e t h e y i n c l u d e d other interventions in addition to the c h o l e s t e r o l - l o w e r i n g regimen. No large clinical trial w i t h clinical e n d p o i n t s h a s been reported for CHD patients w i t h low to moderate levels of cholesterol. R E C O M M E N D A T I O N S : The r e c o m m e n d a t i o n to treat CHD

patients w h o h a v e low to moderate levels of c h o l e s t e r o l w i t h diet or drugs is not b a s e d o n c o n v i n c i n g e v i d e n c e of efficacy. This is in clear contrast to the r e c o m m e n d a t i o n for CHD patients with high levels of c h o l e s t e r o l , for w h o m there is def'mitive clinical trial evidence o f b e n e f i t from cholesterollowering therapy. While w e await clinical trial results for CHD patients w i t h low to moderate levels o f c h o l e s t e r o l , c l i n i c i a n s and patients m u s t c o n s i d e r the p o s s i b l e d i s a d v a n t a g e s o f therapy in relation to the u n c e r t a i n benefit. K E Y W O R D S : cholesterol; coronary heart disease; h y p e r c h o -

lesterolemia; practice g u i d e l i n e s . J GEN INTERN MED 1 9 9 5 ; 1 0 : 4 6 4 - - 4 7 1 .

Received f r o m the Section o f General I n t e r n a l M e d i c i n e , Dep a r t m e n t o f Medicine, V e t e r a n s Affairs M e d i c a l Center, a n d the University o f M i n n e s o t a School o f Medicine, M i n n e a p o l i s , Minnesota. A d d r e s s c o r r e s p o n d e n c e a n d reprint requests to Dr. R u b i n s : Section of General Internal M e d i c i n e (1110), VA M e d i c a l Center, Minneapolis, MN 55417. 464

n 1987 the N a t i o n a l Heart, Lung, a n d Blood InstiI tute's newly formed National Cholesterol E d u c a t i o n Program (NCEP) i s s u e d its highly i n f l u e n t i a l g u i d e l i n e s for t r e a t m e n t of a d u l t s who have h i g h blood cholesterol. The NCEP h a s n o w i s s u e d a revised set of t r e a t m e n t r e c o m m e n d a t i o n s reflecting n e w d a t a a c c u m u l a t e d over the past several years. 1.2 One of the m a j o r revisions involves the t r e a t m e n t r e c o m m e n d a t i o n for p a t i e n t s with establish~d c o r o n a r y h e a r t disease (CHD). The guidelines set a goal for low-density l i p o p r o t e i n cholesterol (LDL-C) of 2.58 mmol/L (100 mg/dL) for p e r s o n s with CHD, a n d r e c o m m e n d t h a t d r u g t h e r a p y s h o u l d be considered w h e n the LDL-C r e m a i n s above 3.36 mmol/L (130 mg/dL) after dietary i n t e r v e n t i o n . ' These levels are 0.78 mmol/L (30 mg/dL) lower t h a n the target a n d d r u g i n i t i a t i o n levels specified in the o r i g i n a l report. 3 There are two practical i m p l i c a t i o n s of this recomm e n d a t i o n . The first is t h a t p e r s o n s with CHD a n d high levels of LDL-C ( > 4 . 1 3 mmol/L, 160 mg/dL) will have to be treated more aggressively, often w i t h m u l t i p l e drugs, to lower their LDL-C levels to below 2.58 mmol/L (100 mg/dL}. The s e c o n d i m p l i c a t i o n , a n d the focus of t h i s paper, is t h a t p e r s o n s with CHD a n d low to m o d e r a t e levels of LDL-C (2.58 to 4.13 mmol/L, 100 to 160 rag/ dL), who were previously n o t treated or were treated with diet alone, will n o w be categorized as h a v i n g elevated blood cholesterol a n d will be c a n d i d a t e s for t r e a t m e n t . T h u s , u n d e r the n e w g u i d e l i n e s , it is e s t i m a t e d t h a t 10 million A m e r i c a n s w i t h CHD will be eligible for dietary therapy to lower t h e i r LDL-C levels a n d t h a t 4 million will ultimately be c a n d i d a t e s for d r u g t h e r a p y to a t t a i n the LDL-C goal. 4 Since lipid-lowering t h e r a p y o n t h i s scale will entail considerable cost a n d i n c o n v e n i e n c e a n d m a y also e n t a i l some toxicity, it is i m p o r t a n t to carefully e x a m i n e the s t r e n g t h of the s u p p o r t i n g d a t a for t h i s n e w guideline. Specifically, w h a t is the evidence t h a t CHD p a t i e n t s w i t h low to moderate levels of LDL-C b e n e f i t from cholesterollowering t r e a t m e n t ? The r a t i o n a l e t h a t the NCEP provides for its t r e a t m e n t r e c o m m e n d a t i o n s for CHD patients focuses o n the evidence s u p p o r t i n g t r e a t m e n t of h i g h levels of cholesterol i n t h i s p o p u l a t i o n , w i t h only p a s s i n g reference to the applicability of these data to

JGIM

Volume 1O, August 1995

p e r s o n s with low to m o d e r a t e levels. With the r e c e n t p u b l i c a t i o n of the S c a n d i n a v i a n S i m v a s t a t i n Survival Study, which s h o w e d a s i g n i f i c a n t r e d u c t i o n i n total mortality for CHD p a t i e n t s with h i g h levels of LDL-C (mean 4.87 mmol/L, 188 mg/dL) t r e a t e d w i t h s i m v a s tatin, there is n o w s t r o n g s u p p o r t for t r e a t i n g CHD patients who have h i g h levels of LDL-C. 5 T h a t study, however, did not address the q u e s t i o n of w h e t h e r cholesterollowering t r e a t m e n t b e n e f i t s p a t i e n t s w i t h low to moderate levels of LDL-C. The p u r p o s e of t h i s paper, therefore, is to provide a s y s t e m a t i c e v a l u a t i o n of t h o s e s t u d ies t h a t specifically p e r t a i n to CHD p a t i e n t s w h o have low to moderate levels of cholesterol, w i t h a special emp h a s i s o n the s t u d i e s cited by the NCEP.

METHODS A c o m p u t e r s e a r c h of the MEDLINE d a t a b a s e from 1966 to 1994 was p e r f o r m e d u s i n g coronary d i s e a s e , cholesterol, controlled clinical trials, a n d cohort s t u d i e s as search terms. In a d d i t i o n , the b i b l i o g r a p h i e s of relevant articles were s c a n n e d for a d d i t i o n a l references. Cohort s t u d i e s were i n c l u d e d w h e n there were at least 100 patients. Clinical trials, i n c l u d i n g t h o s e w i t h angiographic e n d p o i n t s , were i n c l u d e d w h e n t h e r e was a control group. Cholesterol levels are defined i n t h i s p a p e r a c c o r d i n g to the NCEP cutoff p o i n t s , as follows: a h i g h level is defined as a n LDL-C > 4 . 1 3 mmol/L (160 mg/dL); a moderate level as a n LDL-C of 3.36 to 4.13 mmol/L (130 to 160 mg/dL); a low level as a n LDL-C of 2.58 to 3.36 m m o l / L (100 to 130 mg/dL); a n d a very low level as a n LDL-C < 2 . 5 8 mmol/L ( 100 mg/dL). For t h o s e s t u d i e s t h a t report total cholesterol only, a r o u g h e s t i m a t e of the corres p o n d i n g LDL-C c a n be m a d e by s u b t r a c t i n g 70 mg/dL from the total cholesterol i n mg/dL (based o n the Friedewald formula 6 u s i n g average values of h i g h - d e n s i t y lipoprotein cholesterol a n d triglycerides for CHD patients of 40 a n d 150 mg/dL, respectively). Methods u s e d for c a l c u l a t i n g c o n f i d e n c e intervals a n d pooled relative risk are d e s c r i b e d i n the legend of Figure 1.

Cohort Studies There are s e v e n large prospective c o h o r t s t u d i e s of p a t i e n t s with a n t e c e d e n t CHD a n d a wide r a n g e of cholesterol levels at baseline. 7-1a T h e details of the s t u d y d e s i g n s are s h o w n i n Table 1, a n d t h e r e s u l t s (relative risk of e n d p o i n t s for s u b j e c t s who h a d m o d e r a t e compared with low levels of cholesterol) are s h o w n i n F i g u r e 1. Relative risk, as opposed to a b s o l u t e risk, is the m o s t appropriate m e a s u r e to c o n s i d e r b e c a u s e it b e s t approximates the c h a n g e i n r i s k t h a t could be expected with a t r e a t m e n t - i n d u c e d c h a n g e i n cholesterol level. The two m o s t r e c e n t of these s t u d i e s were cited i n the NCEP report. T h e first, from the F r a m i n g h a m Study,12

465

included 374 m e n a n d w o m e n w i t h p r i o r m y o c a r d i a l infarction who were s t r a t i f i e d b y b a s e l i n e total cholesterol level a n d followed for more t h a n t e n years. T h e risk of CHD d e a t h ( a d j u s t e d for m u l t i p l e r i s k factors) was n o t significantly h i g h e r for those who h a d m o d e r a t e levels of total cholesterol (5.17 to 6.21 mmol/L, 200 to 239 mg/ dL) t h a n it was for those who h a d low levels ( < 5 . 1 7 mmol/L, 200 mg/dL) (relative risk 1.4, 95% CI 0.8 to 3.5). For r e c u r r e n t m y o c a r d i a l i n f a r c t i o n , there w a s only a marginally s i g n i f i c a n t i n c r e a s e d risk for t h o s e who h a d moderate c o m p a r e d w i t h low levels (relative risk 2.2, 95% CI 1.0 to 4.9). The s e c o n d cohort s t u d y cited i n the NCEP report, the Lipid R e s e a r c h Clinics Prevalence Study, 13 followed for ten years 471 m e n who h a d CHD. As i n the Fram i n g h a m Study, t h e r e was n o s i g n i f i c a n t i n c r e a s e d r i s k of CHD d e a t h for t h o s e who h a d m o d e r a t e levels of LDLC (3.4 to 4.1 mmoFL, 130 to 160 mg/dL), c o m p a r e d w i t h those who h a d low levels of LDL-C ( < 3 . 4 mmol/L, 130 mg/dL) (adjusted relative risk 3.7, 95% CI 0.8 to 16.6). No myocardial i n f a r c t i o n d a t a were reported. The five o t h e r cohort s t u d i e s also failed to d e m o n strate a s i g n i f i c a n t i n c r e a s e d risk of CHD d e a t h a m o n g p a t i e n t s who h a d m o d e r a t e c o m p a r e d w i t h low cholesterol levels, even t h o u g h these s t u d i e s h a d m u c h larger sample sizes (as reflected b y the n a r r o w e r c o n f i d e n c e intervals i n F i g u r e 1 ). T h e only s t u d y b e s i d e s t h e Fram i n g h a m S t u d y to report m y o c a r d i a l i n f a r c t i o n s , the Coronary D r u g Project, 8 f o u n d a m a r g i n a l l y s i g n i f i c a n t increased risk for the c o m b i n e d e n d p o i n t (CHD d e a t h a n d myocardial i n f a r c t i o n ) for p e r s o n s who h a d m o d erate c o m p a r e d w i t h low cholesterol at b a s e l i n e (relative risk 1.2, 95% CI 1.0 to 1.54). In s u m m a r y , n o n e of the cohort s t u d i e s of p a t i e n t s with e s t a b l i s h e d CHD s h o w s t h a t a m o d e r a t e level of cholesterol confers a s i g n i f i c a n t l y i n c r e a s e d r i s k of CHD death, c o m p a r e d w i t h a low level of cholesterol. However, the pooled relative risk of 1.14 (95% CI 1.08 to 1.4) for the five s t u d i e s i n w h i c h s u f f i c i e n t raw d a t a are r e p o r t e d suggests a small b u t s i g n i f i c a n t i n c r e a s e i n CHD d e a t h for those p a t i e n t s who h a d m o d e r a t e vs low cholesterol levels (Fig. 1). It s h o u l d be n o t e d t h a t n o n e of t h e s e studies c o m p a r e d o u t c o m e s for p e r s o n s who h a d low cholesterol w i t h t h o s e of p e r s o n s who h a d very low levels.

Clinical Trials There h a s b e e n n o large clinical trial d e s i g n e d to d e t e r m i n e w h e t h e r cholesterol-lowering diets or d r u g s reduce clinical e v e n t s (myocardial i n f a r c t i o n a n d CHD death) a m o n g p a t i e n t s w i t h CHD a n d low to m o d e r a t e levels of cholesterol. T h e m e a n cholesterol level at baseline was high i n all the major secondary p r e v e n t i o n trials, i n c l u d i n g the six cited i n the NCEP r e p o r t ~6-22 a n d the recently completed S c a n d i n a v i a n s i m v a s t a t i n trial ( m e a n baseline LDL-C 4.87 mmol/L, 188 mg/dL], s T h e only trial to e x a m i n e o u t c o m e s a m o n g lipid s u b g r o u p s was the

466

Rubins, Cholesterol and Coronary Heart Disease

Frarningham

=

0

I

Framingham (MI)

1

LRC

I

i

BRHS

]GIM

$

i

,It

I

O

AMIS (ages 55-69) AMIS (ages 30-55)

=

Goteborg (total mortality)

;

0

;

CDP (CHDdeath and MI)

CDP Whitehall

¢

Total ,

0,5

=

I

2

i

I

,

I

3 4 Relative Risk (95%CI)

I

5

/~(

I

17

FIGUREt. Relative risks and 95% confidence intervals (CIs] for coronary heart disease (CHD] death in CHD patients who had moderate compared with low baseline cholesterol levels. See Table 1 for details of the design, reference, and definitions of moderate and low cholesterol subgroups for each study. See the reference list for complete reference citations. Relative risks and 95% CIs were taken directly from the published report for the Framingham Study12and the Lipid Research Clinics [LRC] Prevalence Study.13In both cases, the relative risks were adjusted for age and other risk factors. For all other studies, crude relative risks and 95% Cls [Taylor series14] were calculated from the published incidence data. For the Aspirin Myocardial Infarction Study (AMIS], incidence data were extrapolated from figures 1 and 3." Total refers to the ManteI-Haenszel pooled relative risk~5based on data from the five studies in which sufficient raw data were available?-~6 BRHS = British Regional Heart Study1°; CDP = Coronary Drug ProjectS; MI = myocardial infarction.

Coronary Drug Project's 15-year follow-up for total mortality. ~ In this s t u d y t h e r e was a s i g n i f i c a n t r e d u c t i o n in total mortality for p a t i e n t s t r e a t e d w i t h n i a c i n compared with placebo. W h e n the s u b g r o u p ( n -- 2,058) w h o had total cholesterol levels less t h a n 6 . 4 6 mmol/L (250 mg/dL) at b a s e l i n e were a n a l y z e d separately, however, there was no significant difference i n total mortality rates between the n i a c i n - a n d the p l a c e b o - t r e a t e d p a t i e n t s . Since there are n o clinical trial d a t a with " h a r d " e n d p o i n t s i n this p o p u l a t i o n , i n t e n s e i n t e r e s t h a s focused o n the s t u d i e s i n w h i c h a n g i o g r a p h i c a l l y determ i n e d atherosclerotic c h a n g e i n the c o r o n a r y arteries c o n s t i t u t e d the p r i m a r y e n d p o i n t . T h e NCEP report cites six s u c h trials,19. 23-27 b u t only o n e of t h e s e involved a p o p u l a t i o n whose average LDL-C at b a s e l i n e was less t h a n 4.13 mmol/L (160 mg/dL) 26 a n d o n e reported results for a s u b g r o u p w h o h a d m o d e r a t e levels of cholesterol at baseline. 23 T h e r e are four a d d i t i o n a l trials of p a t i e n t s with m o d e r a t e levels of cholesterol, 28-3~ t h r e e of which were p u b l i s h e d since the NCEP report.29-31 These six trials are reviewed below. I n all t h e o t h e r m a j o r a n giographic trials, the m e a n b a s e l i n e LDL-C was h i g h , above 4.39 mmol/L ( 170 mg/dL) for all a n d closer to 5.17 (200 mg/dL} for m o s t (Table 2).

Angiographic Trials o f P a t i e n t s w i t h M o d e r a t e Levels of LDL-C. The Lifestyle H e a r t Trial (LHT) 2~ was a small study of 48 m e n a n d w o m e n w i t h a n g i o g r a p h i c a l l y docu m e n t e d c o r o n a r y artery d i s e a s e who were r a n d o m i z e d to either u s u a l care or a n i n t e n s e lifestyle m o d i f i c a t i o n program t h a t i n c l u d e d a very-low-fat diet, stress m a n a g e m e n t t r a i n i n g , s m o k i n g c e s s a t i o n , aerobic exercise, a n d g r o u p s u p p o r t . The m e a n b a s e l i n e LDL-C of 3.92 mmol/L (151 mg/dL) was r e d u c e d to 2.46 mmol/L (95 mg/dL) i n the active t r e a t m e n t group. C h a n g e i n coronary atherosclerosis was a s s e s s e d after o n e year by repeat c o r o n a r y a n g i o g r a p h y i n 41 p a t i e n t s . The average percentage d i a m e t e r s t e n o s i s decreased s i g n i f i c a n t l y i n the active t r e a t m e n t group, while the u s u a l care g r o u p experienced a s i g n i f i c a n t i n c r e a s e i n c o r o n a r y stenosis. The Heidelberg Trial 2s enrolled 1 13 m e n who h a d documented coronary artery stenoses a n d randomized them to a n i n t e r v e n t i o n c o n s i s t i n g of i n t e n s i v e physical exercise a n d a low-fat, low-cholesterol diet or to u s u a l care. The m e a n LDL-C of 4.24 mmol/L (164 mg/dL) at baseline declined to 3.85 mmol/L (149 mg/dL) i n the active t r e a t m e n t group. T h e r e was s i g n i f i c a n t l y less progression of c o r o n a r y d i s e a s e i n the i n t e r v e n t i o n g r o u p t h a n there was i n the c o n t r o l g r o u p (assessed b y q u a n -

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10, A u g u s t

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1995

Table t Prospective Cohort Studies in Coronary Heart Disease Patients

Study*

Year of Publication

N

Baseline Cholesterol Groupsm mmol/L [mg/dl]

Follow.up [years]

Low <5.17 (<200)

F r a m i n g h a m 12

1991

260 men, 114 w o m e n

10.5

LRC Prevalence ~a

1990

471 m e n

10.1

Moderate 5.17-6.21

LDL-C+

(200-239)

LDL-Ca¢

<3.4

(<130)

3.4-4.1

(130-159)

(<224)

5.8-6.7

(224-259)

BRHS m

1988

428 men

7.5

<5.8

AMIS l'

1987

1,930 men (ages 55-69)

3.0

<5.09 (<197)

5.09-5.61

(197-217)

AMIS 11

1987

2,091 men 30-55)

3.0

<5.27 (<204)

5.27-5.81

(204-225)

Goteborg 9

1984

1,204 m e n

7.0

--<5.99 ( < 2 3 2 )

6.0-6.69

(232-259)

CDP ~

1978

2,789 men

5.0

<5.56 (<215)

5.56-6.15

(215-238)

Whitehall 7

1977

2,700 m e n

5.0

<4.62 (<180)

4.62-5.63

(180-219)

(ages

*For c o m p l e t e reference citations, s e e t h e reference list. LRC = Lipid R e s e a r c h Clinics; B R H S = British R e g i o n a l H e a r t S t u d y ; AMIS = A s p i r i n Myocardial Infarction S t u d y ; CDP = Coronary Drug Project. ÷LDL-C = l o w - d e n s i t y lipoprotein cholesterol.

Table 2 Mean Baseline Low.density Lipoprotein Cholesterol [LDL-C] in Major Angiographic Studies Baseline LDL-C-mmol/L {mg/dL]~

Year of Publication

Nt

Follow-up years

HARP a~

1994

79

2.5

Multiple m e d i c a t i o n s

3 . 6 2 (140)

MAAS 32

1994

345

4.0

Simvastatin

4 . 3 8 (170)

Study*

Intervention

SCRIP 3°

1994

246

4.0

Multiple i n t e r v e n t i o n s

4 . 0 9 (158)

CCAIT 33

1994

299

2.0

Lovastatin

4 . 4 7 (173)

MARS ~9

1993

247

2.0

Lovastatin

3.91 (151)

Heidelberg 28

1992

92§

1.0

P h y s i c a l e x e r c i s e a n d low-fat diet

4 . 2 4 (1641

STARS 2s

1992

74§

3.5

Cholestyramine; Low-fat diet

5 . 2 6 (204) 5 . 0 0 (194)

FATS 24

1990

120§

2.5

L o v a s t a t i n a n d colestipol; Niacin a n d colestipol

5 . 0 8 (197) 4 . 9 2 (190)

LHT 26

1990

41

1.0

Multiple lifestyle i n t e r v e n t i o n s

3 . 9 2 ( 151 )

POSCH ~

1990

838

9.7

Partial ileal b y p a s s s u r g e r y

4 . 6 2 (179)

SCOR 27

1990

72

2.0

Combined drug regimens

7 . 3 2 (283)

CLAS 23

1987

162§

2.0

Colestipol a n d n i a c i n

4 . 4 2 ( 171 )

NHLB134

1984

I 16

5.0

Cholestyramine

6 . 2 5 (242)

*For c o m p l e t e reference citations, s e e t h e reference list. All s t u d i e s w e r e controlled. T h e S T A R S a n d F A T S trials h a d t w o i n t e r v e n t i o n a r m s . ÷Evaluable p a t i e n t s . #In the t r e a t m e n t group. §Men only. HARP = Harvard Atherosclerosis R e v e r s i b i l i t y Project; MAAS = M u l t i c e n t e r A n t i - A t h e r o m a S t u d y ; S C R I P = S t a n f o r d C o r o n a r y R i s k I n t e r v e n t i o n Project; CCAIT = C a n a d i a n Coronary Atherosclerosis I n t e r v e n t i o n Trial; M A R S = Monitored A t h e r o s c l e r o s i s R e g r e s s i o n S t u d y ; S T A R S = St. T h o m a s ' Atherosclervsls R e g r e s s i o n S t u d y ; F A T S = F a m i l i a l Atherosclerosis T r e a t m e n t S t u d y ; L H T = L i f e s t y l e H e a r t Trial; P O S C H = P r o g r a m o n t h e S u r g i c a l Control of t h e H y p e r l l p i d e m t a s ; S C O R = Arteriosclerosis S p e c i a l i z e d C e n t e r o f R e s e a r c h I n t e r v e n t i o n Trial: CLAS = C h o l e s t e r o l - L o w e r i n g Atherosclerosls S t u d y ; a n d NHLBI = N a t i o n a l Heart, L u n g , a n d B l o o d Institute.

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Table 3 Side Effects, Costs, and Compliances of Various Drug Regimens for Management of Low to Moderate Low-density Lipoprotein Cholesterol [LDL-C] Pretreatment LDL-Cmmmol/ L [mg/dl)

Target Reduction* [%]

3.36 {130)

3.62 (140)

4.13 (160)

23

29

38

Side Effects? Regimen (Daily Dose)

Common

Serious

Niacin, 3 g

Flushing/pruritus Headache Gastrointestinal

Hepatitis (rare)

Lovastatin, 20 mg

Gastrointestinal Sleep disturbances

LFT¶] abnormalities (0.1%)

Colestipol, lOg

Constipation

Lovastatin, 40 mg

Gastrointestinal

Colestipol, 20 g

Constipation

Lovastatin, 80 mg

Gastrointestinal Sleep disturbances

LFT abnormalities (1.5%) Myopathy (0.2%)

Colestipol, 20 g, and niacin, 3 g

Constipation Flushing/pruritus Headache Gastrointestinal

Hepatitis (rare)

Sleep disturbances

LFT abnormalities (0.9%) Myopathy (0.1%)

Cost/ Months [$)

Compliance? [%)

3.45

60-70§

59.90

80-90

43.30

?

107.81

80-90

86.60

60-70§

215.62

80-90

90.05

?

*To a c h i e v e LDL-C <<-2 . 5 8 m m o l / L (100 mg/dL). +Data describing serious s i d e effects a n d c o m p l i a n c e for l o v a s t a t i n b a s e d on E x p a n d e d Clinical E v a l u a t i o n o f L o v a s t a t i n (EXCEL) S t u d y . ~ ~:~ iCosl to p h a r m a c i s t b a s e d on a v e r a g e w h o l e s a l e price listings in: Drug Topics R e d Book. M o n t v a l e , NJ: M e d i c a l E c o n o m i c s D a t a , 1994. §See S c h e c t m a n et al. a~ % F T = liver f u n c t i o n test.

titative m e a s u r e m e n t of m i n i m a l a n d relative d i a m e t e r s of s t e n o t i c c o r o n a r y lesions) a m o n g 92 s u b j e c t s after o n e year. Th e M o n i t o r e d A t h e r o s c l e r o s i s R e g r e s s i o n S t u d y (MARS), 29 p u b l i s h e d after th e release of th e NCEP report, enrolled 270 m e n a n d w o m e n w h o h a d a n g i o g r a p h i c a l l y defined c o r o n a r y a r t e r y d i s e a s e a n d r a n d o m i z e d t h e m to e i t h e r l o v a s t a t i n (40 m g twice a day) or placebo. T h e m e a n b a s e l i n e LDL-C w a s 3.91 m m o l / L (151 m ~ d L ) , w h i c h was r e d u c e d to 2.41 m m o l / L (93 mg/dL) in t h e lovastatin group. C h a n g e in c o r o n a r y a t h e r o s c le r o si s was a s s e s s e d a n g i o g r a p h i c a l l y a f te r two y e a r s in 24 7 patients, with the p r i m a r y e n d p o i n t defined as c h a n g e from baseline in average p e r c e n t a g e d i a m e t e r s t e n o s i s . T h e r e was no s i g n i f i c a n t difference b e t w e e n th e t r e a t m e n t g r o u p s for t h e p r i m a r y e n d p o i n t (p > 0.20), a l t h o u g h there was s i g n i f i c a n t i m p r o v e m e n t in favor of th e lovastatin g r o u p in a s e c o n d a r y e n d p o i n t ( m e a n global c h a n g e score by e x p e r t p an e l review). T h e S t a n f o r d C o r o n a r y R i s k I n t e r v e n t i o n Project (SCRIP) 3° enrolled 3 0 0 m e n a n d w o m e n w h o h a d coronary a r t e r y s t e n o s e s d o c u m e n t e d by a n g i o g r a p h y a n d r a n d o m i z e d t h e m to e i t h e r u s u a l care or a n i n t e n s i v e , m u l t i f a c t o r i a l r i s k - r e d u c t i o n p r o g r a m . In t h e a c t i v e

t r e a t m e n t g r o u p t h e m e a n LDL-C of 4.09 mmol/L (158 mg/dL) was r e d u c e d to 3.12 m m o l / L (121 mg/dL). T h e p r i m a r y a n g i o g r a p h i c e n d p o i n t , c h a n g e in the m i n i m a l d i a m e t e r of visibly d i s e a s e d s e g m e n t s , w as a s s e s s e d in 246 p a t i e n t s after four years, by a n g i o g r a p h e r s " ge nerally blinded" to the subject's t r e a t m e n t group. The riskr e d u c t i o n g r o u p e x p e r i e n c e d a s i g n i f i c a n t l y lower r a t e of coronary n a r r o w i n g t h a n did t h e u s u a l care group. Th e H a r v a r d A t h e r o s c l e r o s i s Reversibility Project (HARP) 3 ~r a n d o m i z e d 79 n o r m o c h o l e s t e r o l e m i c p a t i e n t s who h ad CHD to e i t h e r a n i n t e n s i v e s t e p p e d r e g i m e n designed to lower total c h o l e s t e r o l to below 4.1 m m o l / L (160 mg/dL) or placebo. T h e m e a n LDL-C of 3.62 m m o l / L (140 mg/dL) at b a s e l i n e w as r e d u c e d to 2.23 m m o l / L (86 mg/dL) in t h e active t r e a t m e n t group. Repeat coronary a r t e r i o g r a p h y at 2.5 y e a r s d e m o n s t r a t e d no difference b e t w e e n t h e t r e a t m e n t g r o u p s by an y m e a s u r e of a n g i o g r a p h i c disease. T h e r e w a s n o c o r r e l a t i o n b e t w e e n c h a n g e in lipids a n d l e s i o n size. As expected (based o n t h e i r s h o r t d u r a t i o n a n d s m a l l sample sizes), n o n e of t h e s e trials s h o w e d an y significant difference b et w een the t r e a t m e n t a n d control g r o u p s in clinical e v e n t s ( i n c l u d i n g d e a t h , m y o c a r d i a l infarction, u n s t a b l e a n g i n a , c a r d i a c ar r est , a n d c a r d i a c re-

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Volume 10, August 1995

v a s c u l a r i z a t i o n procedures). In a d d i t i o n to these s t u d ies, the Cholesterol-Lowering Atherosclerosis S t u d y 2~ subdivided its p o p u l a t i o n (average baseline LDL-C of 4.42 retool/L, 171 mg/dL) into t h o s e who h a d low a n d t h o s e who had h i g h total cholesterol levels at b a s e l i n e [4.81 to 6.24 mmol/L ( 185 to 240 mg/dL), m e a n 5.62 mmol/L (216 mg/dL) vs 6.26 to 9.10 mmol/L (241 to 350 mg/dL), m e a n 7.02 mmol/L (270 mg/dL)]. S i g n i f i c a n t i m p r o v e m e n t i n a n g i o g r a p h i c disease was n o t e d for the d r u g - t r e a t e d patients in b o t h the low- a n d high-cholesterol s u b g r o u p s compared w i t h the c o r r e s p o n d i n g placebo groups. In s u m m a r y , there are five p u b l i s h e d a n g i o g r a p h i c studies in p o p u l a t i o n s with CHD a n d m o d e r a t e levels of cholesterol at baseline. T h e LHT i n c l u d e d only 41 patients followed for one year a n d involved a very s t r i n g e n t , multifactorial lifestyle i n t e r v e n t i o n p r o g r a m t h a t would be difficult to r e p r o d u c e in u s u a l clinical s e t t i n g s a n d that may have h a d o t h e r beneficial effects aside from cholesterol lowering.26 T h e SCRIP w a s also a trial of m u l tiple r i s k - r e d u c t i o n i n t e r v e n t i o n s ; w h e t h e r the beneficial effect seen a m o n g t h e t r e a t e d p a t i e n t s was d u e to the LDL-C r e d u c t i o n or to s o m e o t h e r c o m p o n e n t of the program is u n k n o w n . 3° T h e Heidelberg Trial d e m o n strated a n g i o g r a p h i c b e n e f i t w i t h a diet a n d exercise program t h a t r e d u c e d LDL-C only modestly {8%) a n d to a level (3.85 mmol/L, 149 mg/dL) far above the NCEP goal of 2.58 mmol/L ( 100 mg/dL). T h i s m o d e s t r e d u c t i o n , taken together with the o b s e r v a t i o n t h a t there was n o correlation b e t w e e n c h a n g e i n cholesterol a n d anglographic i m p r o v e m e n t , a g a i n raises the i s s u e of w h e t h e r a n o t h e r c o m p o n e n t of t h i s m u l t i f a c t o r i a l i n t e r v e n t i o n m i g h t have b e e n r e s p o n s i b l e for the a n g i o g r a p h i c imp r o v e m e n t . F u r t h e r m o r e , t h e i n c r e a s e d r i s k of lifet h r e a t e n i n g a r r h y t h m i a s a s s o c i a t e d w i t h the exercise c o m p o n e n t of the i n t e r v e n t i o n raises c o n c e r n s a b o u t the safety of this p a r t i c u l a r p r o g r a m . 28 T h e HARP d e m o n strated no a n g i o g r a p h i c b e n e f i t from i n t e n s i v e lipid-lowering t h e r a p y i n a g r o u p of CHD p a t i e n t s whose average baseline LDL-C was 3.62 mmol/L (140 mg/dL). 3~ Finally, the MARS d e m o n s t r a t e d n o i m p r o v e m e n t i n c o r o n a r y stenoses w i t h l o v a s t a t i n t r e a t m e n t by its p r i m a r y outcome m e a s u r e . ~9 It is difficult to k n o w how to i n t e r p r e t the "positive" f i n d i n g i n the s e c o n d a r y o u t c o m e meas u r e m e n t in this trial, s i n c e the relative accuracy, reliability, a n d predictive value of the v a r i o u s a n g i o g r a p h i c measures of coronary stenosis are still u n c e r t a i n . 35 T h u s , even if the d a t a from the a n g i o g r a p h i c trials clearly favored t r e a t m e n t , the a p p r o p r i a t e n e s s of u s i n g angiographic o u t c o m e s as s u r r o g a t e m a r k e r s for CHD d e a t h a n d myocardial i n f a r c t i o n w o u l d still n e e d to be established.

CONCLUSIONS Despite i n t r i g u i n g p o p u l a t i o n s t u d i e s a n d laboratory data s u g g e s t i n g t h a t very low levels of cholesterol may be ideal, 36, 37 the available c o h o r t s t u d i e s a n d short-

469

term clinical trials do n o t s u p p o r t the h y p o t h e s i s t h a t lowering low to m o d e r a t e levels of cholesterol to very low levels p r e v e n t s r e c u r r e n t CHD events. F o r t u n a t e l y , large clinical trials specifically d e s i g n e d to a d d r e s s t h i s i s s u e are now u n d e r way, w i t h r e s u l t s expected i n the n e x t several years. 38 In the m e a n t i m e , how s h o u l d the available d a t a be used to help g u i d e clinical d e c i s i o n m a k i n g ? We m u s t insist, to b e g i n with, t h a t g u i d e l i n e s be developed with "evidence-based" m e t h o d s . 39 It is m i s l e a d i n g a n d ultimately c o u n t e r p r o d u c t i v e to p r e s e n t g u i d e l i n e s t h a t do not clearly d i s t i n g u i s h b e t w e e n t h o s e r e c o m m e n d a t i o n s strongly s u p p o r t e d by the evidence (e.g., to treat CHD p a t i e n t s who have h i g h cholesterol) a n d those with little s u p p o r t i n g evidence {e.g., to t r e a t CHD p a t i e n t s who have l o w to m o d e r a t e cholesterol). T h e r e is g r o w i n g fear that, i n the era of h e a l t h care reform, practice g u i d e l i n e s will be u s e d as coercive i n s t r u m e n t s (e.g., b y i n s u r e r s , a d m i n i s t r a t o r s , a n d litigators) to i n f l u e n c e clinical practice. 4° It is therefore i m p e r a t i v e t h a t they be developed by rigorous m e t h o d s a n d f o r m u l a t e d i n precise language, a n d t h a t they explicitly a c k n o w l e d g e u n c e r t a i n t y where it exists. In the a b s e n c e of s t r o n g evidence of efficacy, clinicians need to c o n s i d e r m a n y factors, i n c l u d i n g the patient's age, comorbidity, a n d "activity" of CHD (e.g., time since most recent myocardial i n f a r c t i o n ) as well as the cost, i n c o n v e n i e n c e , side effects, a n d toxicity of the proposed medical r e g i m e n . T a b l e 3 lists the costs, side effects, a n d c o m p l i a n c e s a s s o c i a t e d w i t h v a r i o u s r e g i m e n s that m i g h t be r e q u i r e d to lower a n LDL-C of 3.36 m m o l / L (130 mg/dL), 3.62 mmol/L (140 mg/dL), or 4.13 m m o l / L (160 mg/dL) to less t h a n 2.58 mmol/L (100 mg/dL). Although formal c o s t - e f f e c t i v e n e s s a n a l y s e s have generally favored m e d i c a l m a n a g e m e n t of cholesterol for seco n d a r y p r e v e n t i o n , 44 it is i m p o r t a n t to r e m e m b e r t h a t these analyses focus o n p a t i e n t s w i t h h i g h levels of cholesterol. It is likely t h a t the i n c r e m e n t a l c o s t - e f f e c t i v e ness of a policy t h a t e x t e n d s cholesterol-lowering treatm e n t to those w i t h low to m o d e r a t e levels w o u l d be considerably less favorable. In c o n c l u s i o n , it s h o u l d be r e c o g n i z e d t h a t the reco m m e n d a t i o n to treat CHD p a t i e n t s who have low to moderate levels of cholesterol w i t h diet or d r u g s to further reduce s e r u m cholesterol is n o t b a s e d o n solid clinical trial data. T h i s is i n clear c o n t r a d i s t i n c t i o n to the r e c o m m e n d a t i o n to t r e a t m a r k e d l y h y p e r c h o l e s t e r o lemic p a t i e n t s who have CHD, a r e c o m m e n d a t i o n b a s e d on c o n v i n c i n g o b s e r v a t i o n a l s t u d i e s a n d clinical trial data t h a t d e m o n s t r a t e t h a t cholesterol-lowering regim e n s reduce r e c u r r e n t m y o c a r d i a l i n f a r c t i o n s , CHD death, a n d total m o r t a l i t y 45 a n d are cost-effective. 44 T h e e x c i t e m e n t over the s t r i k i n g r e s u l t s of the S c a n d i n a v i a n S i m v a s t a t i n Survival S t u d y s h o u l d n o t o b s c u r e the fact that the p a t i e n t s i n t h a t trial h a d h i g h levels of LDL-C ( m e a n 4.87 mmol/L, 188 mg/dL) a n d t h a t t h e r e s u l t s may therefore n o t be applicable to those w h o have lower

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Rubins, Cholesterol and Coronary Heart Disease

levels, s While patients nicians

we await

with and

patients

sible disadvantages tain

the

clinical

low to moderate must

weigh

of therapy

trial results

levels

for CHD

of cholesterol,

for themselves in relation

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benefit.

The author thanks Joanne Karvonen, MA, for manuscript preparation.

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terol concentration and coronary heart disease tn population with low cholesterol concentrations. BMJ. 1991;303:276-282. Sacks FM, Pfeffer MA, Moye L, et al, Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: the Cholesterol and Recurrent Events Trial (CARE). Am J Cardiol. 1991 ;68:1436-46. Woolf SH. Practice guidelines, a new reality in medicine. Arch Intern Med. 1992;152:946-52. Kassirer JP. The quality of care and the quality of measuring it. N Engl J Med. 1993;329:1263-5. Schectman G, Hiatt J, Hartz A. Evaluation of the effectiveness of lipid-lowering therapy (bile acid sequestrants, niacin, psyllium and lovastatin) for treating hypercholesterolemia in veterans, Am J Car-

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ANNOUNCEMENT ABIM Board Eligibility T h e A m e r i c a n B o a r d of I n t e r n a l Medicine is p l a n n i n g to u n d e r t a k e a c o m p l e t e review of its policies c o n c e r n i n g B o a r d eligibility. T h e ABIM a n t i c i p a t e s t h a t r e v i s e d B o a r d eligibility policies will be a n n o u n c e d b y D e c e m b e r 31, 1996. In the i n t e r i m , t h e r u l e s c o n c e r n i n g t h e d u r a t i o n a n d r e e s t a b l i s h m e n t of t h e B o a r d eligible s t a t u s will be s u s p e n d e d . All c a n d i d a t e s w i t h t h i s s t a t u s will c o n t i n u e to be r e g a r d e d a s Board-eligible a n d t h e r e f o r e able to s i t for t h e Certifying E x a m i n a t i o n s in i n t e r n a l m e d i c i n e or t h e s u b s p e c i a l i t i e s . However, t h e B o a r d ' s Q u a l i f y i n g E x a m i n a t i o n , developed to r e e s t a b l i s h B o a r d eligibility, will n o t be offered. C a n d i d a t e s w h o h a v e q u e s t i o n s a b o u t t h i s policy s h o u l d c o n t a c t t h e A m e r i c a n B o a r d of I n t e r n a l Medicine, 3 6 2 4 M a r k e t Street, P h i l a d e l p h i a , PA 1 9 1 0 4 - 2 6 7 5 ; 1-800-441-2246.

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