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Results of intensive long-term treatment of familial hypercholesterolemia
Results of Intensive Long-Term Treatment of Familial Hypercholesterolemia Kjetil Retterstcdl, MD, Marie Stugaard, MD, PhD, Christine and Leiv Ose, MD, PhD
Gsrbitz,
BSI,
Fii-seven patients with familial hypercholesterolemia (FH) with mean age of 48 years (mnge 30 to 69), participated in a follow-up examination 5.5 years after the completion of a 1-year trial with lovastatin, cholestyramine, probucol, or o-3 fatty acids. The goals were to record quality of life, compliance to treatment, adverse effeck, and clinical outcome. The quality of life was similar to that in a Norwegian reference population. The factors causing most distress to patienk were keeping a diet low in satumted fuk, taking medication, and fear of death. The medication was mostly prescribed in maximum dosages. At follow-up, the reduction in total cholesterol was 36% (p <0.05), low-density lipoprotein (LDL) cholesterol 38% (p <0.05), triglycerides 20% (p ~0.05) compared with being on diet therapy only. Highdensity lipoprotein (HDL) cholesterol increased 8% (p ~0.05). Intake of saturated and monounsaturated fat increased 1.5% and 1.7% (p <0.05), respectively; pofy-
unsaturated fat was unchanged. Three patients experienced myocardial infarction, of whom 2 died and 1 developed angina pectoris. Before the start of lovastatin treatment, 27 coronary events occured per 1,000 patient-years in this group compared with 12 events per 1,000 patient-years thereafter. Of 28 patients reporting adverse events, 4 discontinued lovastatin and 3 discontinued cholestyramine. Several practical and psychological difficulties were associated with FH. long-term intensive lipid-lowering therapy was possible in FH outpatients without loss of effect and with good compliance to therapy. Intensive therapy, today is, however, not sufficient for many FH patients to reach a therapeutic goal of LDL cholesterol ~4.0 mmol/l.. More potent lipidlowering agents are needed. 0 1996 by Excerpta
amilial hypercholesterolemia (FH) is an autosomal dominant disorder with premature coronary F heart disease.’ Regression of arteriosclerotic lesions
METHODS
has been shown in FH patients by Kane and coworkers,2 and aggressive treatment has shown to be cost beneficial.’ Thus, it is a paradox that <20% of these patients received 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors in 1995.4 A recent study5 showed that cholesterol lowering therapy with a HMG CoA reductase inhibitor reduced total mortality by 30% in patients with coronary heart disease and total cholesterol between 5.5 and 8.0 mmol/L. Another recent study6 showed a 22% reduction in overall mortality using HMG CoA reductase inhibitor treatment in men with total cholesterol levels at >7 mmol/L and no history of myocardial infarction. Since placebo-controlled survival studies like this5T6cannot be performed in FH patients due to ethical considerations, other study designs, like the present follow-up study, must be applied. The objectives of the present study were to investigate quality of life, coronary events, and the ability to comply with intensive drug and diet therapy. A plasma concentration of N-terminal proatrial natriuretic factor, used as a biochemical marker of impaired heart function,7.* was also evaluated in these high risk FH patients. From the Lipid Clinic, Medical Department A, Rikshospitalet, Oslo, Norway. This study was supported in part by a grant from MSD (Norge] A/S. Manuscript received February 15, 1996; revised manuscript received and accepted June 14, 1996. Adress for reprints: Kjetil Retterstcal, Institute of Clinical Biochemistry, Rikshospitalet, 0027 Oslo, Norway.
0 1996 by Excerpta Medica, All rights reserved.
Inc.
Medica, Inc. (Am J Cardiol
1996;78: 1369- 1374)
Study population: During a Smonth period in 1987, all patients with FH who consulted the Lipid Clinic, The National Hospital, Oslo, Norway, were asked to participate in a l-year cholesterol lowering trial. The diagnosis was established by low-density lipoprotein (LDL) cholesterol >5 mmol/L, the presence of xanthomas, and autosomal dominant transmission or expression in childhood.’ Sixty-four patients were included in the trial, and agreed to participate. Four patients were later excluded, 2 due to adverse events, and 2 did not come for their appointments. The remaining 60 patients, 28 men and 32 women, completed a 1-year trial” with lovastatin mono- or combination therapy using cholestyramine, probucol, or w-3 fatty acids. The patients were then followed either as outpatients at the Lipid Clinic, at the local hospital, or by their local physician. Of the 60 patients, 26 men and 31 women were included in a follow-up examination after a total of 5.5 years intensive lipid-lowering treatment. During this period, 2 patients died from myocardial infarction, and 1 was not willing to participate in the follow-up for personal reasons. Nearly half of the patients had coronary heart disease (Tables I and II). Patients with a history of typical exertional angina pectoris with documentation of coronary atherosclerosis/myocardial ischemia or a previous myocardial infarction were defined as having coronary heart disease. Examination: Chest x-rays, exercise electrocardiograms, laboratory analyses, and clinical examinations were performed at the time of follow-up. Angina pectoris was classified according to New York Heart Association classification.” The patients had 0002.9 149/96/s 15.00 PII 50002.9 149(96)00649-2
1369
r
General Health Questionnaire-scores (O-O-1- 1; maximum 30 points possible). laboratory methods: Venous samples were colB/F B/F lected after a 12 to 15 hour overnight fast, and serum Women B/F was separated. Serum total cholesterol, high-density No. of Patients (n9;6) (n = 30) Total lipoprotein (HDL) cholesterol and triglycerides were Coronary heart disease 17/17 9/10 26/27 measured enzymatically. LDL cholesterol was calDaily smokers 17/16 817 9/9 culated using the Friedewald formula.‘6 LipoproHypertension 3/3 3/A 6/7 tein(a) measurement was carried out with an enzyMean age at followup was 48 years (range 30 to 69). Patients were defined moimmunoassay, and a traditional Eliza method os hypertensive only if fhey received antihypertensive therapy. using a TintElise kit (Biopool, Sweden). Readings of the microtiter plate filter were performed as end point measureTABLE II Clinical Vascular Findings at Follow-Up ments (492 nm). The analyses of N-terminal proaNot trial natriuretic factor were perNo. of Patients Normal Pathologic Assessable Totol formed by radioimmunoassay diExercise electrocardiogram A7 7 2 56 rectly in plasma as described by Chest x-ray 50 5 0 55 Sundsfjord et a1.17All analyses in Cardiac auscultation 34 ia 3 55 Carotic auscultation A7 a 0 55 this study were performed at the Femoral auscultation A7 a 0 55 same laboratory with unchanged methods. Electrocardiographic pathologic exercise = ST depression of >2 mm in r2 leads. Pathologic chest xray = enlarged heart conhe. Pathologic ouxultaGon = murmur. Statistics:Mean values with 95% confidence interval were used except for lipoprotein(a) and body mass index where median values and ranges were TABLE Ill Medication used. For univariate comparision of laboratory data, End of Student’s t tests were performed (paired for within No. of Patients 1 -Year Trial Follow-Up group analyses and unpaired for between group analyses). Baseline data (diet therapy only) were comLovastotin 50 33 Lovastatin + probucol 7 13 pared with data at follow-up examination, otherwise Lovastotin + ocipimox 0 2 as indicated in the text. The comparisons between Lovastotin + ocipimox + probucol 0 2 the coronary heart disease patients and the noncoProvastotin 0 2 ronary heart disease patients were performed using Fenofibrate 0 1 Resin monotherapy 0 3 Wilcoxon’s signed rank unpaired test for lipoproNo medication 0 1 tein(a) and N-terminal proatrial natriuretic factor valSum of patients 57 57 ues, for which correlation analyses were done using Potients using resin medication 22 19 Pearson’s r. For all comparisons, a p value 10.05 Lovastatin dosage: 80 mg, resin dosage: 16 g/day at the end of 1 year trial. (2-sided) was considered statistically significant. TABLE I Characteristics and Follow-Up (F)
of the Study Population
at Baseline
(B)
1
I
At follow-up, for resins: probucol
the dosages
for lovostotin
were
80 mg (n = 43). 40 mg (n = 7),
8 g [II = 7), 12 g (n = 61, 16 g (n = 5) ond 24 g/day dosage
brate dosage
was
was 300
1 g, the ocipimox
dosage
was 750
(n = 1). The
mg, and the fenofi-
RESULTS
mg/day.
been individually instructed by a clinical nutritionist to follow a lipid-lowering diet according to American Heart Association step-I.” Dietary compliance was assessed by 4 days of weight dietary records with calculations based on the Norwegian food table. The last dietary record in the drug trial was compared to an equal record at the follow-up examination. Patients filled in an anonymous, 2-part questionnaire. The first part consisted of 20 open questions about FH (e.g.,‘ ‘What is your major concern as a FH patient?“). The second part consisted of 2 standard quality of life tests. Test 1 (Hospital Anxiety and Depression Scale) used 14 questions to detect fear and depression levels,13*14 and was calculated by Like&scores (O-l-2-3; maximum 42 points possible). Test 2 was Goldberg’s general health questionnaire designed to measure psychological and psy30,14*15 chiatric distress. It was evaluated with Goldberg’s 1370
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Compliance: All 57 patients reported good compliance with the lipid-lowering therapy after 5.5 years of treatment. Thirty-one patients had changed part of their medication (Table III). Two patients changed from lovastatin to pravastatin due to probable side effects, and 3 patients reduced lovastatin from 80 to 40 mg/day. Three patients stopped intake of cholestyramine. Six patients reduced cholestyramine intake from 16 to 12 g/day, and 7 patients reduced intake from 16 to 8 g/day. F&e patients began receiving probucol 1 g/day and 4 patients began receiving acipimox 750 mg/day. One patient changed from lovastatin and cholestyramine combination therapy to fenofibrate monotherapy. Quality of life: The patients’main concerns on having FH are listed in Table IV. The scores of the 2 standard life quality tests13-15were within the scores of a Norwegian reference population. However, patients with coronary heart disease indicated slightly more fear and depression than those without in the DECEMBER
15,
1996
cc
TABLE IV Major
Concerns
Related
1
to Familial
Lipid-Lowering
No. of Patients
PI
(“4
Diet
15 (26)
Abdominal
1 A (25)
Nervous
Fear
10 (18)
Musculoskeletal
of death
Low
FH to their
social
Passive
children
acceptance
of food
habits
smoking
Answers question
5 (91
Skin
5 (91
Total
2 (3)
* Tiredness
6 (10)
Other
SU”l
57
about
the 1 major
TABLE V Changes
Fifty-seven
concern
related
in Physical
patients
with FH were asked an open
to FH.
Activity
improved
15 (26)
13 (23)
Unchanged
28
33
Worsened
13 (23)
report
1
Sum
57
Fifty-seven
patients
with familial
physical
fitness and physical
intensive
lipid-lowering
(49)
PI
(58)
2 (31 57 (100)
(100)
before
(“A)
9 (16)
hypercholesterolemia
activity
1
Fitness and Activity
Fitness (%)
Answers
10 (17)
8 (14 6 (1 1)
system*
4 (71 28 (49)
(n = 3); dizziness
(n = 2). headache
(n = 1); nightmare
(n = 1);
taste and smell (n = 1).
(100)
This open question from o questionnaire.
Adverse Events After 5.5 Years of Treatment
No. of Patients
Medication
Transferring
No
TABLE VI Self-reported Intensive
Hypercholesterolemia
were asked about
their
the start of and after 5.5 years
of
therapy.
Hospital Anxiety and Depression Scale test, although it is not statistically significant (p = 0.08). Reports of physical activity and fitness levels are recorded in Table V. Fourteen patients reported decreased sexual activity during the 5.5 years, including 4 men with decreased virility. Although not specifically asked, many patients stated that they felt safer when receiving lipid-lowering treatment. When asked an open anonymous question about evaluating the treatment as outpatients, 11 would have preferred more frequent cholesterol tests, 7 complained of insufficient information on the side effects of drug therapy, and 5 reported apparent ignorance or inexperience regarding FH at the local hospital or physician. Approximately two-thirds of the patients were examined once a year by the lipid clinic, and in addition, many of these had blood tests taken at their local hospital or by their physician. The others were followed by the local physician, except for 2 patients had no follow-up examinations. Adverse effects: Four patients discontinued use of lovastatin due to possible adverse effects (skin itching, finger paresthesias, tinnitus, and nightmare) (Table VI). Of 22 patients using resins, 3 stopped due to possible gastrointestinal side effects. In total, 28 patients reported adverse effects that they associated with the lipid-lowering medication. Patients taking lovastatin combined with resins reported an adverse effect rate of 70% compared with 25% among patients using lovastatin monotherapy. From baseline until 12 weeks of lovastatin 80-mg monotherapy, alanine amino transferase increased
or anything
was asked of 57 patients:
you suspect of being
on adverse
“Do
you have adverse
effect from lipid-lowering
effects, medica.
tion?”
from 23.2 to 29.1 (p <0.05), and further to 30.0 U/ L (p = NS) after 5.5 years. At follow-up 6 patients (11%) had alanine amino transferase exceeding the upper reference value of the laboratory (50 U/L), but the values were below 100 U/L. The aspartate amino transferase values remained stable at all examinations. Diet: Changes were seen in the intake of dietary fat at the follow-up. After l-year treatment, the patients received an average 22% of the total calories from fat; at the follow-up examination this was increased to 26% (p <0.05). The increased consumption of fat was primarily accounted for by higher intake of saturated and monounsaturated fat. The saturated fat increased from 7% of the total calories to 8% (p <0.05), and the monounsaturated fat increased from 7% to 9% (p <0.05). The intake of polyunsaturated fat was unchanged and accounted for 5% of the calories. To analyze the relation between changes in the diet and the blood lipids, only patients receiving stable medication were studied. Nineteen patients using 80 mg/day lovastatin as monotherapy throughout the 5.5 years had completed dietary records at both time points. In this group, the total calories from saturated fat increased from 7.0% to 8.7% (p <0.05), monounsaturated fat increased from 7.4% to 8.8% (p <0.05), and the calories from polyunsaturated fat was unchanged. Using Keys’ formula,” the dietary change only predicted a rise in cholesterol of 0.1 mmol/L,, whereas the actual rise was 0.4 mmol/L in these patients. Lipid values: Serum lipids after 12 weeks of lovastatin monotherapy were not significantly different from values after 5.5 years (Table VII). Among 21 patients receiving consistent lovastatin (80 mg/day) monotherapy no significant change was seen in mean LDL cholesterol between 12 weeks and 5.5 years of treatment. The total cholesterol values were not different in patients with or without coronary heart disease; the values were 9.5 (8.6 to 10.5) and 10.0 mmol/L (9.3 to 10.7), respectively, at baseline (NS), and 6.2 (5.5 to 6.8) versus 6.6 mmol/L (6.0 to 7.1), respectively, at follow-up (NS). Accordingly, LDL cholesterol and HDL cholesterol did not differ between the 2 groups.
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TABLE VII S-Lipids at Baseline,
After
12 Weeks,
and After 5.5 Years of Lipid-Lowering
Therapy % Change
A
Time Whole study population (n = 56*) Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Lovastatin 80 mg/day monotherapy consistent throughout 5.5 yr (n = 21) Total
9.7 7.3
cholesterol
LDL cholesterol HDL cholesterol
Mean
did not take lipid-lowering
values
triglyceride
with
= 88.5
A = baseline
95% confidence
intervals cholesterol
(diet therapy
LDL = low-density
1 mmol/L only);
(5.8-6.7)
6.3
(5.9-6.7)
-35.9
-35.6
0.0001
NS
(4.2-5.0)
4.6
(4.1-4.9)
-37.0
-37.6
0.0001
NS
(1.2-l
1.3
11.2-l
,4)
1.2
(1.1-1.4)
1.1
(0.9-l
.2)
1.2
(1.0-l
9.0 6.6
(8.1-9.9)
5.8
(5.0-6.7)
6.2
(5.7-7.5)
4.2
(3.4-5.0)
4.5
1.2
(1.0-l
1.3
(1.1-1.5)
1 .l
(0.9-l
.6)
(0.9-l
.3)
(1.1-1.9)
1 .O (0.8-l
because
Students
of o temporary
paired
.4) .3) infection
0.019
NS
-24.1
10.3 -19.6
0.0001
NS
(5.3-7.1)
-35.0
-30.1
0.0001
0.046
(3.6-5.3)
-35.9
-31.9
0.0001
NS
0.0008
NS
0.003
NS
.3)
11.0 ,4)
and was not included
f test was used for statistical
8.2
comparisons.
-31.9
15.3 -26.0
in lipid analyses. Values
ore given
in millimole
per liter.
treatment.
HDL = highdensity
1 mmol/L
= 8.6 mg/dl.
B = 12 weeks
lovastotin
80 mg/doy
monotherapy;
C = 5.5 years
intensive
lipid-lowering
lipoprotein
lipoprotein.
TABLE VIII Coronary
Events at Baseline
(6) and Follow-Up
B/F Men, n= 17
No. of Patients Myocardial
B vs C
6.3
(1.1-1.2)
ore given.
A vs B
4.6
drugs ot follow-up
mg/dl,
C vs A
(6.7-7.8)
1.4
1.5
Triglycerides * One patient
B vs A
(9.2-10.3)
1.2
1 .l
C
B
p Values
infarction
13/13
Angioplasty or bypass grafting Angina pectoris
12/13
W6
coronary events was thus 26 patients/16 years = 27 events per B/F Total, 1,000 patient-years before baseline n = 27 compared to 4 patients/55 years = 12 events per 1,000 patient years af17/17 ter. 16/18 13/14 Other clinical events: Twentyseven of 57 patients had xanthomas at baseline. The finger extensors and the heels were particularly affected. Partial or total regression of the xanthomas were reported by 16 patients, and no change in size reported by 11 patients. Nobody reported enlargement of xanthomas. The 3 following incidents were also reported: 1 patient developed diabetes mellitus type II, 1 hypertension, and 1 colon cancer during the 5.5 years. Furthermore, there was an increase in body mass index for both men and women. The increase in men was from 24.8 (range 17 to 29) to 26.2 kg/m2 (range 22 to 43) (p <0.05), and for women from 22.5 (range 18 to 29) to 23.8 kg/m2 (range 17 to 29) (p <0.05). One chronically overweight man had an increase from 27 to 43 kg/m2. However, in an average western population body mass index will usually increase with age.20s21 N-terminal proatrial natriuretic factor: Eight patients had values more than the age adjusted reference values. Patients with coronary heart disease had 780 pmol/L (617 to 942) compared with 550 pmol/L (482 to 618) (p ~0.05) in patients without coronary heart disease. None of the patients had clinically detectable heart failure at follow-up. No relation was found between N-terminal proatrial natriuretic factor and body mass index, blood pressure or lipids, but there were correlation with age (r = 0.45, p <0.05) and screatinine (r = 0.45, p <0.05), as reported by other investigators7
(F)
B/F Women, n= 10 4/4 4/5
7/8
The median lipoprotein(a) value at follow-up was higher in those patients with coronary heart disease (250 mg/L [298 to 6281) than in those patients without (123 mg/L [129 to 2771) (p <0.05), as found in other FH studies.” Lipoprotein(a) was not measured at baseline. Coronary events: A total of 4 coronary events occurred during the 5.5-year period (Table VII). One man (59 years) and 1 woman (39 years) died of myocat-dial infarction, 4 and 2 years, respectively, after lovastatin medication was started. They had received cholestyramine 8 g/day for 4 to 5 years previously. At the start of the study, both had angina pectoris (New York Heart Association classification II and III, respectively), and both had experienced myocardial infarction previously. Another man, who had myocardial infarction at the age of 26, experienced a new one at the age of 31. A 57-year-old woman with no previous cardiac symptoms developed angina pectoris New York Heart Association classification II. Three of 13 patients with angina pectoris at baseline reported less symptoms, 6 remained unchanged, and 2 reported increased symptoms (Table VIII). None of these had any invasive cardiovascular intervention performed. Two other patients had percutaneous transluminal coronary angioplasty performed successfully. The first symptoms of coronary heart disease among the FH patients in the present study arose 16 DISCUSSION Results from this long-term follow-up study of years before baseline of the drug trial. At baseline, 26 patients had coronary heart disease, of whom 17 FH outpatients indicate that intensive lipid-lowering had experienced myocardial infarction. The rate of treatment was safe, and had a permanent lipid-low1372
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ering effect. The compliance to treatment was good, tensin-converting enzyme inhibitors (n = 1). The deand quality of life was comparable to a reference crease may also be related to optimized dosages of the medications already received. However, the mapopulation’s. Compliance: It has been reported that only 7% to jor common change to all patients was the aggressive 20% of dyslipemic patients continued to take lipid- lipid-lowering treatment. In recent studies, treatlowering medication after l-year treatment.** All 57 ments with simvastatin and pravastatin have reduced patients in the present study reported good compli- the incidence of myocardial infarction and death ance after 5.5 years. Since patients reported anony- from coronary heart disease in both patients with esmously, there should be no reason for them to falsify tablished coronary heart diseases and in men with their results. The reason for this good compliance moderate hypercholesterolemia.6 If one estimates could be the very high motivation in those patients 1,000 FH patients to have been included in the preswith a genetic disorder. Repeated lifestyle advice ent study, 27 would experience coronary events per was also considered to be important. Interestingly, year before statin treatment compared to 12 after even in this group, 28% were still smoking daily treatment. Similarly, with 1,000 patients in 4S5 and compared with the 30% 5.5 years earlier. Continuing WOSCOPS,6 42 and 18 coronary events, respeclipid-lowering medication and a diet according to tively, would occur per year in the placebo group, American Heart Association step II2 was thus easier compared with 18 and 13, respectively, in the treatto follow than to quit smoking. The maximum dos- ment group. Our results indicate a low rate of coroages of lovastatin, probucol, and acipimox did not nary events in a high-risk population with or without represent any major problems for most patients, even coronary heart disease, when treated intensively with in combination therapy, but resins did present with lipid-lowering therapy. However, without a control group the power of qualitative data are insufficient. more problems. N-terminal proatrial natriuretic factor: Elevated NQuality of life: The standard life quality tests13-15 were used at follow-up only. Therefore, we can only terminal proatrial natriuretic factor, which is assoconclude that the scores were within the reference ciated with impaired cardiac function,7%xwas related range of a normal population. However, a prevoius to the presence of coronary heart disease among FH lovastatin/placebo study23 showed no influence of patients. Therefore, N-terminal proatrial natriuretic treatment on life quality. The main distress associ- factor may serve as a screening marker for impaired ated with the treatment of FH was to keep a diet low cardiac function in FH patients. HMG-CoA reducin saturated fat. Diet is still an important part of the tase inhibitors inhibit synthesis of ubiquinone (cotreatment of FH, but positive information about enzyme Q) as well as cholesterol synthesis,27 and healthy and appetizing food is more encouraging serum ubiquinone decreasesparallel to cholesterol.** Ubiquinone is essential in the intramitochondrial than using a restrictive tone. As in other autosomal dominant inherited dis- electron transport, which is the main source of eneases,24patients may feel guilt by transferring their ergy in all cells of the body.29 Some authors27*30 have FH gene to their children. Having experienced early suggested that depletion of ubiquinone in the myodeaths in the family, patients may also feel anger at cytes may be involved in the pathogenesis of heart their own parents for transferring the FH gene to failure. N-terminal proatrial natriuretic factor, as a them. It is important that patients realize that treat- measure of impaired cardiac function, should inment today is much more effective than a few years crease if the myocytes were depleted in ubiquinone, ago. according to hypotheses in previous studies27-29In Diet: Although a significant change in nutritional the present study, the 30 patients without detectable fat intake was seen during the 5.5 years, the diet still coronary heart disease had values within the agemet the goals of the American Heart Association step adjusted reference level. HMG CoA reductase inhibI lipid-lowering diet.12 Saturated fat accounted for itor treatment during 5.5 years thus did not result in 8.2% of the total calorie intake at follow-up, while N-terminal proatrial natriuretic factor values more the American Heart Association step I diet requires than the age-adjusted reference values.
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3. Goldman L, Goldman PA, Williams LW, Weinstein MC. Cost-effectiveness considerations in the treatment of heterozygous familial hypercholesterolemia with medications. Am J Cardiol 1993;72:75D-79D. 4. Williams RR, Hamilton-Craig I, Kostner GM, Hegele RA, Hayden MR, Pimstone SN, Faergman 0, Schuster H, Steinhagen-Thiessen E, Beisiegel U, Keller C, Czeizel AE et al. In: Berg K, Boulyjenkov V, Christen Y eds. Genetic Approaches to Noncommunicable Diseases. Berlin Heidelberg: Springer-Verlag, 1996:35-45. 5. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4s). Lancer 1994;344:1383-1389. 6. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307. 7. Hall C, Roleau JL, Moye L, de Champlain J, Bichet D, Sussex B, Packer M, Roulea J, Arnold MO. N-terminal proatrial natriuretic factor. An independent predictor of long-term prognosis after myocardial infarction. Circulation 1994,89: 1934- 1942. 8. Lerman A, Gibbons RJ, Rodelheffer RJ, Bailey KR, McKinley LJ, Heublein DM, Burnett JC Jr. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction. Lmcet 1993;341:1105-1109. 9. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Striver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, vol III. New York: MC Graw-Hill. 1994;1981-2030. 10. Stugaard M, Wiig I, Ose L, Nordseth J,. Familial hypercholesterolemia. Intensive diet therapy combined with drug therapy. Tidsskr Nor Laegeforen 1992;112:2642-2646. 1 I. Hackett TP, Cassem NH. Psychologic aspects of rehabilitation following myocardial infarction. In: Wenger NK, Hellerstein HK eds. Rehabilitation of the Coronary Patient. New YorkWiley & Sons, 1978:243-253. 12. American Heart Association. Recommandation for the treatment of hypercholesterolemia. Circulation 1986;69:1065A-1090A. 13. Mourn T, Ssrensen T, Nzss S, Holmen J. Changes in quality of life caused by being diagnosed as hypertensive or other events in life. Tidsskr Nor Lageforen1992;112:18-23. 14. Malt UF, Mogstad TE, Refnin IB. Goldbergs general health questionnaire. Tidsskr Nor Lmgeforen1989;109:1391-1394. 15. Huppert FA, Walters DE, Day NE, Elliot BJ. The factor stmctare of the general health questionnaire (Goldgergs general health questionnaire-30). A re-
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liability study on 6317 community residents. Br J Psychiatry 1989; 155:178185. 16. Friedewal WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without the use of the preparative ultrasentrifuge. Clin Chem 1972;18:499-502. 17. Sundsfjord JA, Thibault G, Larochelle P, Cantin M. Identification and plasma concentration of the N-terminal fragment of proatrial natriuretic factor in man. .I Clin Endocrinol Metab 1988;66:605-610, 18. Keys A, Anderson JT, Grande F. Prediction of serum-cholesterol respons of man to changes in fats in the diet. Lmcet 1957;2:959-966. 19. Dahlen GH. Lp(a) lipoprotein in cardiovasculer disease. Atherosclerosis 1994;108:11-26. 20. Rolland Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A. Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 1991;45:13-21. 21. Casey V, Dwyer JT, Coleman AK, Valadin I. Body mass index from childhood to middle age: a 50-y follow-up. Am J Clin Nutr 1992;56:14- 18. 22. Gotto AM. Overview of current issues in management of dyslipidemia. Am J Cardiol 1993;71:3B-8B. 23. Downs JR, Oster G, Santanello NC. HMG-CoA reductase inhibitors and quality of life. JAMA 1993;269:3107-3108. 24. Tibben, A, Frets PG. Van de Kamp JJ, Niermeijer MF, Vegtervan der Vlis M, Roos RA, Rooymans HG, van Ommen GJ, Verhage F. On attitudes and appreciation 6 months after predicting DNA testing for Huntington disease in the Dutch program. Am J Med Genet 1993;48: 103- 111. 25. Lovastatin Study Group I Trough IV. Lovastatin 5-year safety and efficiacy study Arch Zntem Med 1993;153:1079-1087. 26. International Task Force for Prevention of Coronary Heart Disease. Prevention of coronary heart disease: scientific background and new clinical guidlines. Recqmmandations of the European Atherosclerosis Society. Nutr Metab Cardiovasc Dis 1992;2: 113- 156. 27. Folkers, K. Lovastatin decreases coenzyme Q levels in humans. Proc Natl .Sci USA 1990;87:8931-8934, 28. Nohl H, Jordan W, Yongman RJ. Quinones in biology, functiones in electron transfer and oxygen activation. Adv Free Rad Biol Med 1986;2:211-279. 29. Greenberg S, Frishman WH, Co-enzyme QIO: a new drug for cardiovascular disease. J Clin Phmmacol 1990;30: 596-608. 30. Laaksonen R, Ojala JP, Tikkanen MJ, Himberg JJ. Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1994;46:313-317.
DECEMBER 15, 1996
Gsrbitz,
BSI,
Fii-seven patients with familial hypercholesterolemia (FH) with mean age of 48 years (mnge 30 to 69), participated in a follow-up examination 5.5 years after the completion of a 1-year trial with lovastatin, cholestyramine, probucol, or o-3 fatty acids. The goals were to record quality of life, compliance to treatment, adverse effeck, and clinical outcome. The quality of life was similar to that in a Norwegian reference population. The factors causing most distress to patienk were keeping a diet low in satumted fuk, taking medication, and fear of death. The medication was mostly prescribed in maximum dosages. At follow-up, the reduction in total cholesterol was 36% (p <0.05), low-density lipoprotein (LDL) cholesterol 38% (p <0.05), triglycerides 20% (p ~0.05) compared with being on diet therapy only. Highdensity lipoprotein (HDL) cholesterol increased 8% (p ~0.05). Intake of saturated and monounsaturated fat increased 1.5% and 1.7% (p <0.05), respectively; pofy-
unsaturated fat was unchanged. Three patients experienced myocardial infarction, of whom 2 died and 1 developed angina pectoris. Before the start of lovastatin treatment, 27 coronary events occured per 1,000 patient-years in this group compared with 12 events per 1,000 patient-years thereafter. Of 28 patients reporting adverse events, 4 discontinued lovastatin and 3 discontinued cholestyramine. Several practical and psychological difficulties were associated with FH. long-term intensive lipid-lowering therapy was possible in FH outpatients without loss of effect and with good compliance to therapy. Intensive therapy, today is, however, not sufficient for many FH patients to reach a therapeutic goal of LDL cholesterol ~4.0 mmol/l.. More potent lipidlowering agents are needed. 0 1996 by Excerpta
amilial hypercholesterolemia (FH) is an autosomal dominant disorder with premature coronary F heart disease.’ Regression of arteriosclerotic lesions
METHODS
has been shown in FH patients by Kane and coworkers,2 and aggressive treatment has shown to be cost beneficial.’ Thus, it is a paradox that <20% of these patients received 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors in 1995.4 A recent study5 showed that cholesterol lowering therapy with a HMG CoA reductase inhibitor reduced total mortality by 30% in patients with coronary heart disease and total cholesterol between 5.5 and 8.0 mmol/L. Another recent study6 showed a 22% reduction in overall mortality using HMG CoA reductase inhibitor treatment in men with total cholesterol levels at >7 mmol/L and no history of myocardial infarction. Since placebo-controlled survival studies like this5T6cannot be performed in FH patients due to ethical considerations, other study designs, like the present follow-up study, must be applied. The objectives of the present study were to investigate quality of life, coronary events, and the ability to comply with intensive drug and diet therapy. A plasma concentration of N-terminal proatrial natriuretic factor, used as a biochemical marker of impaired heart function,7.* was also evaluated in these high risk FH patients. From the Lipid Clinic, Medical Department A, Rikshospitalet, Oslo, Norway. This study was supported in part by a grant from MSD (Norge] A/S. Manuscript received February 15, 1996; revised manuscript received and accepted June 14, 1996. Adress for reprints: Kjetil Retterstcal, Institute of Clinical Biochemistry, Rikshospitalet, 0027 Oslo, Norway.
0 1996 by Excerpta Medica, All rights reserved.
Inc.
Medica, Inc. (Am J Cardiol
1996;78: 1369- 1374)
Study population: During a Smonth period in 1987, all patients with FH who consulted the Lipid Clinic, The National Hospital, Oslo, Norway, were asked to participate in a l-year cholesterol lowering trial. The diagnosis was established by low-density lipoprotein (LDL) cholesterol >5 mmol/L, the presence of xanthomas, and autosomal dominant transmission or expression in childhood.’ Sixty-four patients were included in the trial, and agreed to participate. Four patients were later excluded, 2 due to adverse events, and 2 did not come for their appointments. The remaining 60 patients, 28 men and 32 women, completed a 1-year trial” with lovastatin mono- or combination therapy using cholestyramine, probucol, or w-3 fatty acids. The patients were then followed either as outpatients at the Lipid Clinic, at the local hospital, or by their local physician. Of the 60 patients, 26 men and 31 women were included in a follow-up examination after a total of 5.5 years intensive lipid-lowering treatment. During this period, 2 patients died from myocardial infarction, and 1 was not willing to participate in the follow-up for personal reasons. Nearly half of the patients had coronary heart disease (Tables I and II). Patients with a history of typical exertional angina pectoris with documentation of coronary atherosclerosis/myocardial ischemia or a previous myocardial infarction were defined as having coronary heart disease. Examination: Chest x-rays, exercise electrocardiograms, laboratory analyses, and clinical examinations were performed at the time of follow-up. Angina pectoris was classified according to New York Heart Association classification.” The patients had 0002.9 149/96/s 15.00 PII 50002.9 149(96)00649-2
1369
r
General Health Questionnaire-scores (O-O-1- 1; maximum 30 points possible). laboratory methods: Venous samples were colB/F B/F lected after a 12 to 15 hour overnight fast, and serum Women B/F was separated. Serum total cholesterol, high-density No. of Patients (n9;6) (n = 30) Total lipoprotein (HDL) cholesterol and triglycerides were Coronary heart disease 17/17 9/10 26/27 measured enzymatically. LDL cholesterol was calDaily smokers 17/16 817 9/9 culated using the Friedewald formula.‘6 LipoproHypertension 3/3 3/A 6/7 tein(a) measurement was carried out with an enzyMean age at followup was 48 years (range 30 to 69). Patients were defined moimmunoassay, and a traditional Eliza method os hypertensive only if fhey received antihypertensive therapy. using a TintElise kit (Biopool, Sweden). Readings of the microtiter plate filter were performed as end point measureTABLE II Clinical Vascular Findings at Follow-Up ments (492 nm). The analyses of N-terminal proaNot trial natriuretic factor were perNo. of Patients Normal Pathologic Assessable Totol formed by radioimmunoassay diExercise electrocardiogram A7 7 2 56 rectly in plasma as described by Chest x-ray 50 5 0 55 Sundsfjord et a1.17All analyses in Cardiac auscultation 34 ia 3 55 Carotic auscultation A7 a 0 55 this study were performed at the Femoral auscultation A7 a 0 55 same laboratory with unchanged methods. Electrocardiographic pathologic exercise = ST depression of >2 mm in r2 leads. Pathologic chest xray = enlarged heart conhe. Pathologic ouxultaGon = murmur. Statistics:Mean values with 95% confidence interval were used except for lipoprotein(a) and body mass index where median values and ranges were TABLE Ill Medication used. For univariate comparision of laboratory data, End of Student’s t tests were performed (paired for within No. of Patients 1 -Year Trial Follow-Up group analyses and unpaired for between group analyses). Baseline data (diet therapy only) were comLovastotin 50 33 Lovastatin + probucol 7 13 pared with data at follow-up examination, otherwise Lovastotin + ocipimox 0 2 as indicated in the text. The comparisons between Lovastotin + ocipimox + probucol 0 2 the coronary heart disease patients and the noncoProvastotin 0 2 ronary heart disease patients were performed using Fenofibrate 0 1 Resin monotherapy 0 3 Wilcoxon’s signed rank unpaired test for lipoproNo medication 0 1 tein(a) and N-terminal proatrial natriuretic factor valSum of patients 57 57 ues, for which correlation analyses were done using Potients using resin medication 22 19 Pearson’s r. For all comparisons, a p value 10.05 Lovastatin dosage: 80 mg, resin dosage: 16 g/day at the end of 1 year trial. (2-sided) was considered statistically significant. TABLE I Characteristics and Follow-Up (F)
of the Study Population
at Baseline
(B)
1
I
At follow-up, for resins: probucol
the dosages
for lovostotin
were
80 mg (n = 43). 40 mg (n = 7),
8 g [II = 7), 12 g (n = 61, 16 g (n = 5) ond 24 g/day dosage
brate dosage
was
was 300
1 g, the ocipimox
dosage
was 750
(n = 1). The
mg, and the fenofi-
RESULTS
mg/day.
been individually instructed by a clinical nutritionist to follow a lipid-lowering diet according to American Heart Association step-I.” Dietary compliance was assessed by 4 days of weight dietary records with calculations based on the Norwegian food table. The last dietary record in the drug trial was compared to an equal record at the follow-up examination. Patients filled in an anonymous, 2-part questionnaire. The first part consisted of 20 open questions about FH (e.g.,‘ ‘What is your major concern as a FH patient?“). The second part consisted of 2 standard quality of life tests. Test 1 (Hospital Anxiety and Depression Scale) used 14 questions to detect fear and depression levels,13*14 and was calculated by Like&scores (O-l-2-3; maximum 42 points possible). Test 2 was Goldberg’s general health questionnaire designed to measure psychological and psy30,14*15 chiatric distress. It was evaluated with Goldberg’s 1370
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Compliance: All 57 patients reported good compliance with the lipid-lowering therapy after 5.5 years of treatment. Thirty-one patients had changed part of their medication (Table III). Two patients changed from lovastatin to pravastatin due to probable side effects, and 3 patients reduced lovastatin from 80 to 40 mg/day. Three patients stopped intake of cholestyramine. Six patients reduced cholestyramine intake from 16 to 12 g/day, and 7 patients reduced intake from 16 to 8 g/day. F&e patients began receiving probucol 1 g/day and 4 patients began receiving acipimox 750 mg/day. One patient changed from lovastatin and cholestyramine combination therapy to fenofibrate monotherapy. Quality of life: The patients’main concerns on having FH are listed in Table IV. The scores of the 2 standard life quality tests13-15were within the scores of a Norwegian reference population. However, patients with coronary heart disease indicated slightly more fear and depression than those without in the DECEMBER
15,
1996
cc
TABLE IV Major
Concerns
Related
1
to Familial
Lipid-Lowering
No. of Patients
PI
(“4
Diet
15 (26)
Abdominal
1 A (25)
Nervous
Fear
10 (18)
Musculoskeletal
of death
Low
FH to their
social
Passive
children
acceptance
of food
habits
smoking
Answers question
5 (91
Skin
5 (91
Total
2 (3)
* Tiredness
6 (10)
Other
SU”l
57
about
the 1 major
TABLE V Changes
Fifty-seven
concern
related
in Physical
patients
with FH were asked an open
to FH.
Activity
improved
15 (26)
13 (23)
Unchanged
28
33
Worsened
13 (23)
report
1
Sum
57
Fifty-seven
patients
with familial
physical
fitness and physical
intensive
lipid-lowering
(49)
PI
(58)
2 (31 57 (100)
(100)
before
(“A)
9 (16)
hypercholesterolemia
activity
1
Fitness and Activity
Fitness (%)
Answers
10 (17)
8 (14 6 (1 1)
system*
4 (71 28 (49)
(n = 3); dizziness
(n = 2). headache
(n = 1); nightmare
(n = 1);
taste and smell (n = 1).
(100)
This open question from o questionnaire.
Adverse Events After 5.5 Years of Treatment
No. of Patients
Medication
Transferring
No
TABLE VI Self-reported Intensive
Hypercholesterolemia
were asked about
their
the start of and after 5.5 years
of
therapy.
Hospital Anxiety and Depression Scale test, although it is not statistically significant (p = 0.08). Reports of physical activity and fitness levels are recorded in Table V. Fourteen patients reported decreased sexual activity during the 5.5 years, including 4 men with decreased virility. Although not specifically asked, many patients stated that they felt safer when receiving lipid-lowering treatment. When asked an open anonymous question about evaluating the treatment as outpatients, 11 would have preferred more frequent cholesterol tests, 7 complained of insufficient information on the side effects of drug therapy, and 5 reported apparent ignorance or inexperience regarding FH at the local hospital or physician. Approximately two-thirds of the patients were examined once a year by the lipid clinic, and in addition, many of these had blood tests taken at their local hospital or by their physician. The others were followed by the local physician, except for 2 patients had no follow-up examinations. Adverse effects: Four patients discontinued use of lovastatin due to possible adverse effects (skin itching, finger paresthesias, tinnitus, and nightmare) (Table VI). Of 22 patients using resins, 3 stopped due to possible gastrointestinal side effects. In total, 28 patients reported adverse effects that they associated with the lipid-lowering medication. Patients taking lovastatin combined with resins reported an adverse effect rate of 70% compared with 25% among patients using lovastatin monotherapy. From baseline until 12 weeks of lovastatin 80-mg monotherapy, alanine amino transferase increased
or anything
was asked of 57 patients:
you suspect of being
on adverse
“Do
you have adverse
effect from lipid-lowering
effects, medica.
tion?”
from 23.2 to 29.1 (p <0.05), and further to 30.0 U/ L (p = NS) after 5.5 years. At follow-up 6 patients (11%) had alanine amino transferase exceeding the upper reference value of the laboratory (50 U/L), but the values were below 100 U/L. The aspartate amino transferase values remained stable at all examinations. Diet: Changes were seen in the intake of dietary fat at the follow-up. After l-year treatment, the patients received an average 22% of the total calories from fat; at the follow-up examination this was increased to 26% (p <0.05). The increased consumption of fat was primarily accounted for by higher intake of saturated and monounsaturated fat. The saturated fat increased from 7% of the total calories to 8% (p <0.05), and the monounsaturated fat increased from 7% to 9% (p <0.05). The intake of polyunsaturated fat was unchanged and accounted for 5% of the calories. To analyze the relation between changes in the diet and the blood lipids, only patients receiving stable medication were studied. Nineteen patients using 80 mg/day lovastatin as monotherapy throughout the 5.5 years had completed dietary records at both time points. In this group, the total calories from saturated fat increased from 7.0% to 8.7% (p <0.05), monounsaturated fat increased from 7.4% to 8.8% (p <0.05), and the calories from polyunsaturated fat was unchanged. Using Keys’ formula,” the dietary change only predicted a rise in cholesterol of 0.1 mmol/L,, whereas the actual rise was 0.4 mmol/L in these patients. Lipid values: Serum lipids after 12 weeks of lovastatin monotherapy were not significantly different from values after 5.5 years (Table VII). Among 21 patients receiving consistent lovastatin (80 mg/day) monotherapy no significant change was seen in mean LDL cholesterol between 12 weeks and 5.5 years of treatment. The total cholesterol values were not different in patients with or without coronary heart disease; the values were 9.5 (8.6 to 10.5) and 10.0 mmol/L (9.3 to 10.7), respectively, at baseline (NS), and 6.2 (5.5 to 6.8) versus 6.6 mmol/L (6.0 to 7.1), respectively, at follow-up (NS). Accordingly, LDL cholesterol and HDL cholesterol did not differ between the 2 groups.
PREVENTIVE CARDIOlOGY/lONGTERM
TREATMENT OF HYPERCHOLESTEROLEMIA
1371
TABLE VII S-Lipids at Baseline,
After
12 Weeks,
and After 5.5 Years of Lipid-Lowering
Therapy % Change
A
Time Whole study population (n = 56*) Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Lovastatin 80 mg/day monotherapy consistent throughout 5.5 yr (n = 21) Total
9.7 7.3
cholesterol
LDL cholesterol HDL cholesterol
Mean
did not take lipid-lowering
values
triglyceride
with
= 88.5
A = baseline
95% confidence
intervals cholesterol
(diet therapy
LDL = low-density
1 mmol/L only);
(5.8-6.7)
6.3
(5.9-6.7)
-35.9
-35.6
0.0001
NS
(4.2-5.0)
4.6
(4.1-4.9)
-37.0
-37.6
0.0001
NS
(1.2-l
1.3
11.2-l
,4)
1.2
(1.1-1.4)
1.1
(0.9-l
.2)
1.2
(1.0-l
9.0 6.6
(8.1-9.9)
5.8
(5.0-6.7)
6.2
(5.7-7.5)
4.2
(3.4-5.0)
4.5
1.2
(1.0-l
1.3
(1.1-1.5)
1 .l
(0.9-l
.6)
(0.9-l
.3)
(1.1-1.9)
1 .O (0.8-l
because
Students
of o temporary
paired
.4) .3) infection
0.019
NS
-24.1
10.3 -19.6
0.0001
NS
(5.3-7.1)
-35.0
-30.1
0.0001
0.046
(3.6-5.3)
-35.9
-31.9
0.0001
NS
0.0008
NS
0.003
NS
.3)
11.0 ,4)
and was not included
f test was used for statistical
8.2
comparisons.
-31.9
15.3 -26.0
in lipid analyses. Values
ore given
in millimole
per liter.
treatment.
HDL = highdensity
1 mmol/L
= 8.6 mg/dl.
B = 12 weeks
lovastotin
80 mg/doy
monotherapy;
C = 5.5 years
intensive
lipid-lowering
lipoprotein
lipoprotein.
TABLE VIII Coronary
Events at Baseline
(6) and Follow-Up
B/F Men, n= 17
No. of Patients Myocardial
B vs C
6.3
(1.1-1.2)
ore given.
A vs B
4.6
drugs ot follow-up
mg/dl,
C vs A
(6.7-7.8)
1.4
1.5
Triglycerides * One patient
B vs A
(9.2-10.3)
1.2
1 .l
C
B
p Values
infarction
13/13
Angioplasty or bypass grafting Angina pectoris
12/13
W6
coronary events was thus 26 patients/16 years = 27 events per B/F Total, 1,000 patient-years before baseline n = 27 compared to 4 patients/55 years = 12 events per 1,000 patient years af17/17 ter. 16/18 13/14 Other clinical events: Twentyseven of 57 patients had xanthomas at baseline. The finger extensors and the heels were particularly affected. Partial or total regression of the xanthomas were reported by 16 patients, and no change in size reported by 11 patients. Nobody reported enlargement of xanthomas. The 3 following incidents were also reported: 1 patient developed diabetes mellitus type II, 1 hypertension, and 1 colon cancer during the 5.5 years. Furthermore, there was an increase in body mass index for both men and women. The increase in men was from 24.8 (range 17 to 29) to 26.2 kg/m2 (range 22 to 43) (p <0.05), and for women from 22.5 (range 18 to 29) to 23.8 kg/m2 (range 17 to 29) (p <0.05). One chronically overweight man had an increase from 27 to 43 kg/m2. However, in an average western population body mass index will usually increase with age.20s21 N-terminal proatrial natriuretic factor: Eight patients had values more than the age adjusted reference values. Patients with coronary heart disease had 780 pmol/L (617 to 942) compared with 550 pmol/L (482 to 618) (p ~0.05) in patients without coronary heart disease. None of the patients had clinically detectable heart failure at follow-up. No relation was found between N-terminal proatrial natriuretic factor and body mass index, blood pressure or lipids, but there were correlation with age (r = 0.45, p <0.05) and screatinine (r = 0.45, p <0.05), as reported by other investigators7
(F)
B/F Women, n= 10 4/4 4/5
7/8
The median lipoprotein(a) value at follow-up was higher in those patients with coronary heart disease (250 mg/L [298 to 6281) than in those patients without (123 mg/L [129 to 2771) (p <0.05), as found in other FH studies.” Lipoprotein(a) was not measured at baseline. Coronary events: A total of 4 coronary events occurred during the 5.5-year period (Table VII). One man (59 years) and 1 woman (39 years) died of myocat-dial infarction, 4 and 2 years, respectively, after lovastatin medication was started. They had received cholestyramine 8 g/day for 4 to 5 years previously. At the start of the study, both had angina pectoris (New York Heart Association classification II and III, respectively), and both had experienced myocardial infarction previously. Another man, who had myocardial infarction at the age of 26, experienced a new one at the age of 31. A 57-year-old woman with no previous cardiac symptoms developed angina pectoris New York Heart Association classification II. Three of 13 patients with angina pectoris at baseline reported less symptoms, 6 remained unchanged, and 2 reported increased symptoms (Table VIII). None of these had any invasive cardiovascular intervention performed. Two other patients had percutaneous transluminal coronary angioplasty performed successfully. The first symptoms of coronary heart disease among the FH patients in the present study arose 16 DISCUSSION Results from this long-term follow-up study of years before baseline of the drug trial. At baseline, 26 patients had coronary heart disease, of whom 17 FH outpatients indicate that intensive lipid-lowering had experienced myocardial infarction. The rate of treatment was safe, and had a permanent lipid-low1372
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1996
ering effect. The compliance to treatment was good, tensin-converting enzyme inhibitors (n = 1). The deand quality of life was comparable to a reference crease may also be related to optimized dosages of the medications already received. However, the mapopulation’s. Compliance: It has been reported that only 7% to jor common change to all patients was the aggressive 20% of dyslipemic patients continued to take lipid- lipid-lowering treatment. In recent studies, treatlowering medication after l-year treatment.** All 57 ments with simvastatin and pravastatin have reduced patients in the present study reported good compli- the incidence of myocardial infarction and death ance after 5.5 years. Since patients reported anony- from coronary heart disease in both patients with esmously, there should be no reason for them to falsify tablished coronary heart diseases and in men with their results. The reason for this good compliance moderate hypercholesterolemia.6 If one estimates could be the very high motivation in those patients 1,000 FH patients to have been included in the preswith a genetic disorder. Repeated lifestyle advice ent study, 27 would experience coronary events per was also considered to be important. Interestingly, year before statin treatment compared to 12 after even in this group, 28% were still smoking daily treatment. Similarly, with 1,000 patients in 4S5 and compared with the 30% 5.5 years earlier. Continuing WOSCOPS,6 42 and 18 coronary events, respeclipid-lowering medication and a diet according to tively, would occur per year in the placebo group, American Heart Association step II2 was thus easier compared with 18 and 13, respectively, in the treatto follow than to quit smoking. The maximum dos- ment group. Our results indicate a low rate of coroages of lovastatin, probucol, and acipimox did not nary events in a high-risk population with or without represent any major problems for most patients, even coronary heart disease, when treated intensively with in combination therapy, but resins did present with lipid-lowering therapy. However, without a control group the power of qualitative data are insufficient. more problems. N-terminal proatrial natriuretic factor: Elevated NQuality of life: The standard life quality tests13-15 were used at follow-up only. Therefore, we can only terminal proatrial natriuretic factor, which is assoconclude that the scores were within the reference ciated with impaired cardiac function,7%xwas related range of a normal population. However, a prevoius to the presence of coronary heart disease among FH lovastatin/placebo study23 showed no influence of patients. Therefore, N-terminal proatrial natriuretic treatment on life quality. The main distress associ- factor may serve as a screening marker for impaired ated with the treatment of FH was to keep a diet low cardiac function in FH patients. HMG-CoA reducin saturated fat. Diet is still an important part of the tase inhibitors inhibit synthesis of ubiquinone (cotreatment of FH, but positive information about enzyme Q) as well as cholesterol synthesis,27 and healthy and appetizing food is more encouraging serum ubiquinone decreasesparallel to cholesterol.** Ubiquinone is essential in the intramitochondrial than using a restrictive tone. As in other autosomal dominant inherited dis- electron transport, which is the main source of eneases,24patients may feel guilt by transferring their ergy in all cells of the body.29 Some authors27*30 have FH gene to their children. Having experienced early suggested that depletion of ubiquinone in the myodeaths in the family, patients may also feel anger at cytes may be involved in the pathogenesis of heart their own parents for transferring the FH gene to failure. N-terminal proatrial natriuretic factor, as a them. It is important that patients realize that treat- measure of impaired cardiac function, should inment today is much more effective than a few years crease if the myocytes were depleted in ubiquinone, ago. according to hypotheses in previous studies27-29In Diet: Although a significant change in nutritional the present study, the 30 patients without detectable fat intake was seen during the 5.5 years, the diet still coronary heart disease had values within the agemet the goals of the American Heart Association step adjusted reference level. HMG CoA reductase inhibI lipid-lowering diet.12 Saturated fat accounted for itor treatment during 5.5 years thus did not result in 8.2% of the total calorie intake at follow-up, while N-terminal proatrial natriuretic factor values more the American Heart Association step I diet requires than the age-adjusted reference values.
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