(Hypertension. 1995;25:47-52.)
© 1995 American Heart Association, Inc.
Articles |
Antihypertensive Therapy in Dyslipidemic Men
Effects on Coronary Heart Disease Incidence and Total Mortality
From the First Department of Medicine, Helsinki (Finland) University.
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Abstract |
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Abstract To investigate the influence of antihypertensive therapy and the success of blood pressure control on coronary heart disease incidence and total mortality, we studied dyslipidemic middle-aged men participating in the placebo arm of the Helsinki Heart Study, a randomized coronary primary prevention trial with gemfibrozil. Based on blood pressure level and the presence of antihypertensive therapy at study entry, the participants were classified into four categories. Relative risks of coronary heart disease (nonfatal myocardial infarction or cardiac death) and total mortality during the 5-year trial period were calculated using Cox proportional hazards models. With subjects who were not using antihypertensive drugs and who had normal blood pressure (category I) as reference, the relative risks of coronary heart disease during the trial period were 2.1 (95% confidence interval [CI], 1.3 to 3.3) in untreated hypertensive subjects (category II), 0.9 (95% CI, 0.2 to 3.8) in subjects with successful antihypertensive therapy (category III), and 2.0 (95% CI, 1.0 to 4.1) in subjects who remained hypertensive despite drug therapy (category IV). The relative risks of death were 1.9 (95% CI, 0.9 to 3.9) in category II and 1.0 (95% CI, 0.1 to 7.3) in category III; in category IV subjects, those with unsuccessful antihypertensive therapy, the relative risk was 4.4 (95% CI, 2.0 to 9.6). The excess mortality in this category was due to cardiovascular causes and was clustered in subjects with multiple drug therapy for hypertension control. We conclude that successful antihypertensive therapy in dyslipidemic men reduced coronary heart disease incidence despite its adverse effects on high-density lipoprotein cholesterol and triglycerides. With regard to total mortality, adequate blood pressure reduction had a positive effect, and unsuccessful hypertension control increased total mortality, especially cardiovascular mortality.
Key Words: hypercholesterolemia • coronary heart disease • mortality • antihypertensive therapy
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Introduction |
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Observational epidemiology indisputably demonstrates an association between low blood pressure (BP) and low coronary heart disease (CHD) incidence. However, most intervention trials using pharmacological agents to lower elevated BP have produced inconclusive results and lower-than-expected reductions in CHD, particularly when the preventive measures have been directed against multiple risk factors.1 2 Several explanations have been advanced, ranging from insufficient follow-up times to a J-shaped association between CHD and BP.3 4 5 One of the definite key factors is the degree of BP reduction achieved.6 7 8 9 10 11 The adverse effects of antihypertensive agents offer another explanation. Considering the multifactorial etiology of coronary atherosclerosis,12 this reasoning is relevant because antihypertensive agents, especially diuretics and ß-blockers, have unfavorable effects on serum lipids, including elevation of triglycerides and total cholesterol, reduction of high-density lipoprotein cholesterol (HDL-C), and disturbances in carbohydrate metabolism.13 14 15 16
We investigated this issue by analyzing the effects of antihypertensive therapy on CHD incidence and total mortality. Special attention was focused on BP control, ie, whether or not normotension was achieved. The study population consisted of 2035 participants in the placebo arm of the Helsinki Heart Study (HHS), a randomized coronary primary prevention trial with gemfibrozil in dyslipidemic middle-aged men. The main results in this article are based on the 5-year trial period, but data of the additional 3.5-year posttrial follow-up are also presented.
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Methods |
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Study Population
The HHS was a double-blind, randomized, placebo-controlled trial to test the hypothesis that lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride levels and elevating HDL-C levels with gemfibrozil would reduce the incidence of CHD during the 5-year study period. The study population was screened from 19 000 middle-aged men employed by two government agencies and five industrial companies. The study design, ethical approvals, and primary results have been described in detail previously.17 18 19 The study participants had to fulfill the lipid acceptance criterion of non–HDL-C greater than or equal to 5.2 mmol/L at two consecutive screening visits 8 to 12 weeks apart and no clinical or electrocardiographic (ECG) evidence of CHD. The lipid acceptance criterion selected subjects from the upper end of serum total cholesterol distribution, whereas HDL-C distribution was not very different from that in the total screened population.20 At the third baseline visit, about 4 to 8 weeks after the second screening visit, the participants were randomly allocated to either gemfibrozil (n=2046) or placebo (n=2035). The principal cardiac end points consisted of nonfatal myocardial infarction and cardiac death. Causes of death were estimated from death certificates, hospital records, and autopsy reports.
After the 5-year double-blind study, the participants were followed for an additional 3.5 years, during which they were allowed to choose whether they openly took gemfibrozil or continued to attend the biannual follow-up visits without drug therapy for dyslipidemia. All participants were given dietary counseling for lowering elevated LDL-C levels. About two thirds of subjects in both original randomized groups continued with gemfibrozil. The results of this posttrial follow-up have been published recently.21 22 With regard to mortality results, the follow-up of the entire study cohort is 100%.
BP Levels and Treatment Categories
BP was recorded by the study nurses using calibrated mercury
sphygmomanometers. The recordings were made with subjects in the
sitting position after interviews and before collection of blood
samples. The cuff measured 12x40 cm, and Korotkoff phase V was used to
define diastolic pressure (phase IV when the sounds could be heard
until the end of the scale). All recordings were made at intervals of 5
mm Hg. To reduce the "regression dilution bias,"23
we used the mean of three measurements during the screening period
(average time, 95±21 days) in classifying the subject as either
hypertensive (systolic BP >140 mm Hg and diastolic BP >90 mm Hg) or
normotensive (systolic BP 
140 mm Hg and/or diastolic BP 90
mm Hg). For the main findings in this study, the selection of BP
classification level was not critical. Higher levels resulted in even
smaller numbers and less-stable results accordingly. The participants
were classified into four categories based on the presence of any
antihypertensive agent at study entry and mean baseline BP (category I:
no antihypertensive therapy, BP 140/90 mm Hg; category II: no
antihypertensive therapy, BP >140/90 mm Hg; category III:
antihypertensive therapy, BP 140/90 mm Hg; and category IV:
antihypertensive therapy, BP >140/90 mm Hg).
It should be noted that the HHS had no specific program for the detection and follow-up of hypertension; diagnoses and antihypertensive therapy were the responsibility of the patients' own physicians. Since the HHS was conducted in the 1980s, antihypertensive therapy consisted mainly of thiazide diuretics, ß-blockers, and their combinations. Of the 241 subjects on drug treatment in the original placebo group, 181 were taking a ß-blocker either alone or combined with diuretics and/or vasodilators.
Statistical Methods
For comparison of continuous variables between subgroups, either
the t test or ANOVA was used, and the
2 test was applied to class variables. Incidence
and mortality rates are given per 1000 person years. Relative risk (RR)
was calculated with Cox proportional hazards models including age and
smoking as covariates in the model. Normotensive subjects without
antihypertensive therapy (category I) were used as the reference group
(RR=1) in the calculations. All analyses were based on the
"intention to treat" principle with regard to the originally
randomized study groups.
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Results |
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Coronary Risk Factor Levels
Because of the selection criterion, LDL-C was very high in the study cohort (Table 1). Antihypertensive therapy was associated with lower HDL-C and higher triglyceride levels, but elevated triglycerides were also associated with hypertension itself. However, the occurrence of severe combined dyslipidemia was more prevalent in subjects with antihypertensive therapy. The interconnections between hypertension, obesity, and triglycerides were also evident in this population, because the prevalence of obesity, defined as a body mass index greater than 26 kg/m2, was 7.3% in category I, 18.1% in category II, 15.5% in category III, and 20.7% in category IV.
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The differences in baseline BP levels among the categories (Table 1) remained stable during at least the initial stage of the study. The mean of four measurements during the first year of follow-up was 130/84 mm Hg in category I, 146/94 mm Hg in category II, 136/91 mm Hg in category III, and 148/97 mm Hg in category IV.
Effects on CHD Incidence
CHD incidence rates during the 5-year study period are given in
the Figure. When hypertension was controlled (category
III), the incidence rate was at the level of normotensive subjects
(RR=0.9, 95% confidence intervals [CI], 0.2 to 3.8), whereas
uncontrolled hypertension, either treated (RR=2.0; 95% CI, 1.0 to 4.1)
or untreated (RR=2.1; 95% CI, 1.3 to 3.3), increased the risk in this
population twofold. Extension of the follow-up time to 8.5 years had no
major effect on the results, with the incidence rate being 5.3 per 1000
person years in category I, 12.2 in category II, 8.0 in category III,
and 13.8 in category IV. As stated above, two thirds of the subjects in
the original placebo group started gemfibrozil for the 3.5-year
posttrial follow-up period.
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Effects on Mortality
A total of 43 participants died during the 5-year trial period and
40 during the 3.5-year posttrial follow-up in this particular study
cohort. Table 2 shows the relative risks of death during
the trial period. The pattern of total mortality rates did not change
substantially when the follow-up was extended to 8.5 years (Table 3), with relative risks of death of 2.3 (95% CI, 1.4 to
3.8) in category II, 1.7 (95% CI, 0.5 to 5.5) in category III, and 5.3
(95% CI, 3.0 to 9.3) in category IV.
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Thirty-one (2.5%) of the 1254 men in reference category I died during the 8.5-year follow-up. Only 10 of these 31 deaths were cardiovascular in nature (8 CHD, 1 stroke, and 1 other vascular cause). Of subjects with unsuccessful antihypertensive therapy (category IV), 20 of 165 (12%) died, with 11 deaths due to CHD (5 fatal myocardial infarctions and 6 sudden deaths), 3 to stroke, 3 to malignancy, 2 to accidents/violence, and 1 to other medical causes. The excess of mortality (RR=5.3) in category IV compared with category I was mainly the result of a 10-fold difference in cardiovascular mortality between these groups (Table 3). The incidence of sudden cardiac death increased from 0.3 per 1000 person years in category I to 2.0 in category II, 3.1 in category III, and 4.5 in category IV.
Mortality-Related Factors
Smoking
The effect of smoking on total mortality was greatest in the
untreated normotensive subjects (category I, Table 4),
whereas smoking seemed to have no influence on the very high mortality
in category IV, with rates of 15.2 per 1000 person years in nonsmokers
and 15.0 in smokers.
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Minor ECG Abnormalities
Minor abnormalities in baseline ECG (Minnesota codes 3.1-3, 4-3,
5-3, 7-3, and 9-2) were slightly more prevalent in hypertensive
subjects, with occurrences of 27% in category I, 34% in category II,
20% in category III, and 35% in category IV. However, these
abnormalities had no substantial effects on the differences in
mortality rates. Annual total mortality during the 8.5-year follow-up
in category IV was 10 per 1000 person years in subjects with minor ECG
abnormalities and 13 in subjects with normal ECG.
Antihypertensive Agents
The distribution of antihypertensive agents was similar in both
treated categories III and IV, respectively, with 21% and 23% on
diuretics, 39% and 33% on ß-blockers, and 40% and 45% on
combinations. However, subjects on combination therapy (diuretic plus
ß-blocker and/or vasodilator) in category IV had a mean annual
mortality rate over 8.5 years of 21 per 1000 person years compared with
14 per 1000 in subjects on ß-blockers and 3 per 1000 in subjects on
diuretics only. When analyzed without considering the BP levels
achieved, the annual mortality pattern in the drug categories remained
essentially unchanged: 17 per 1000 person years on combination therapy,
9 per 1000 on ß-blockers, and 5 per 1000 on diuretics. No differences
were found in mortality rates between users of ß-blockers with or
without intrinsic sympathomimetic activity (ISA)—13 per 1000 person
years in users of ISA- and 10 per 1000 in users of ISA+ blockers—but
the numbers are small. Except for triglycerides and HDL-C, there were
no differences in risk factor levels between the antihypertensive drug
categories during the first year of follow-up (Table 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The main finding in this study was that uncontrolled hypertension in this hypercholesterolemic male cohort during a follow-up period of 8.5 years increased CHD rate and total mortality, whereas sufficient lowering of elevated BP reduced the risk close to the level of normotensive subjects. However, subjects on antihypertensive therapy without adequate BP control had a more than fivefold risk of dying of cardiovascular diseases compared with untreated normotensive subjects.
Based on observational studies, it has been estimated that a prolonged difference of approximately 6 mm Hg in diastolic BP is associated with approximately 37% fewer strokes and 27% fewer CHD deaths and nonfatal myocardial infarctions.24 However, in a meta-analysis of the published trials, a reduction of 5 to 6 mm Hg in diastolic BP with antihypertensive agents during a follow-up period of 5 years reduced CHD mortality only 14%, whereas the reduction in stroke incidence was 42%, as expected.25 Several factors have been offered to explain the lower-than-expected CHD reduction, eg, insufficient follow-up times,5 a J-shaped association between CHD and BP,3 and the multifactorial etiology of coronary atherosclerosis with clustering of other risk factors.26 The last alternative is important because it has been suggested that reduction of elevated BP would not be sufficient alone but the cessation of smoking and control of serum lipid abnormalities would also be required.27 28 The adverse effects of antihypertensive agents should be considered in this context, as it has been shown that ß-blockers and diuretics alter the lipid profile unfavorably, at least in short-term studies.
Despite adverse changes in serum lipid levels and carbohydrate tolerance, most of the intervention trials demonstrating reductions in CHD and stroke rates have used diuretics to control elevated BP.29 30 However, we could not demonstrate any effect of diuretics on lipid levels in this hypercholesterolemic male population. The safety of diuretics has been questioned mainly in subjects with ECG abnormalities. In the Multiple Risk Factor Intervention Trial (MRFIT),1 31 the net difference of 3.1 mm Hg in mean diastolic BP at 72 months was not sufficient to create a difference between the experimental groups, whereas a significant increase in CHD mortality was detected in subjects on diuretics who had minor abnormalities in baseline resting ECG. The adverse outcome was the result of an increased rate of sudden cardiac death. Hypokalemia or diuretic dose did not explain the findings.31
Although ß-blockers as a group definitely increase triglyceride levels and lower HDL-C, there may be differences in the individual drugs in this respect.14 The Helsinki Businessmen Study2 32 found increased CHD mortality in the intervention group during the 15-year follow-up, suggesting that treatment with ß-blockers, especially with pindolol, might be the explanation. In that case, the effect would not be mediated by lipids, because pindolol, with its ISA, is one of the ß-blockers causing the smallest number of adverse changes in lipid levels.14 Primary prevention trials in hypertensive subjects with other ß-blockers have demonstrated a slight but significant superiority of at least metoprolol over treatment with diuretics.33 Additional data also indicate that treatment of hypertension with propranolol, oxprenolol, and metoprolol significantly reduces CHD risk in nonsmokers.34 35 36 All these ß-blocking agents with different ancillary properties have been shown to induce the unfavorable lipid changes of elevated triglycerides and lowered HDL-C. Propranolol use has even been associated with the presence of atherogenic small and dense LDL particles.15
Even though mean values are the standard way of describing the levels of continuous variables in study populations, this approach has several problems in the context of hypertension, and other risk factors as well, because a considerable proportion of the treated population does not reach normotension. Even though a clear cutoff point for the increment/reduction in CHD risk does not exist, these "treatment failures" are definitely at increased risk. If the therapy additionally has adverse effects, these are then clustered in "treatment failures." This is exactly what seems to have happened in our study population, which is why the achieved BP is of major importance in analyzing treatment benefits. A report from the Tromso Study37 supports the concept that decreased HDL-C and elevated triglycerides in hypertensive individuals are probably evoked by drugs, whereas our findings in this hypercholesterolemic cohort are somewhat more controversial, with elevated triglyceride levels being associated with both hypertension itself (Table 1) and the use of ß-blockers (Table 4). However, this is in accordance with the data showing triglyceride level to be involved in the interactions between obesity and hypertension, with insulin resistance as a possible common denominator.38 In any case, low HDL-C in this population seemed to result from the use of drugs.
One must question, however, whether the differences in triglyceride and HDL-C levels in our population were sufficient to explain the mortality variations, because the distributions of antihypertensive therapies, minor ECG abnormalities, and smoking habits were rather similar in the treatment categories. The answer is probably negative because of two facts. First, the differences in lipid levels were insufficient to produce the observed CHD differences. For instance, the prevalence of severe combined dyslipidemia (ratio of LDL-C to HDL-C >5 and triglycerides >2.3 mmol/L), an indicator of substantially increased CHD risk39 in this population, was less than twofold in category IV compared with reference category I (11.1% versus 6.6%, Table 1), and the variation in HDL-C (approximately 3%) between treatment categories could maximally produce a difference of 10% in CHD incidence.19 Second and most important, the difference arose from cardiovascular mortality, especially from the increased incidence of sudden death, a cardiac end point closely associated with hypertension.40 However, in contrast to the MRFIT findings, increased cardiovascular mortality in our population was found in subjects with multiple drug therapy, an indirect indicator of a more complicated disease.
Our study has quite obvious shortcomings and limitations. First, the findings are based on a post hoc subgroup analysis, and the small numbers make the results unstable. However, this situation is identical in all published studies, and a prospective study with these objectives will probably never be conducted. Second, the cohort consisted of white hypercholesterolemic men, so the results may not be generalizable to other populations. Third, a study design changing the experimental medication at the end of the double-blind period creates additional problems, especially if the differences in incidences between the originally randomized placebo and gemfibrozil groups are compared in order to test any hypotheses.
Nevertheless, even bearing the restrictions of our analyses in mind, the results clearly demonstrate that successful antihypertensive therapy reduced CHD incidence as well as total mortality. On the other hand, unsuccessful antihypertensive therapy was associated with increased CHD incidence and mortality, especially cardiovascular mortality. This increment was not explained by adverse changes in lipid levels caused by antihypertensive agents but was most probably the result of a more severe disease.
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Acknowledgments |
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This study was supported by a grant from the Paavo Nurmi Foundation (M.M.), Helsinki, Finland.
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Footnotes |
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Reprint requests to Matti Mänttäri, First Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, SF 00290 Helsinki, Finland.
Received June 15, 1994; first decision June 29, 1994; accepted September 14, 1994.
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