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Workshop II-Hypertension trials and meta-analyses: Is there any value for further studies?
Workshop II-Hypertension Trials and Meta-Analyses: Is There Any Value for Further Studies? CO-CHAIRMEN: RICHARDH. GRIMM,JR., M.D., PH.D., AND HENRYBLACK,M.D.
wo meta-analyses of antihypertensive drug trials T suggest that lowering blood pressure has a significant impact in reducing cerebrovascular complications but its effect in preventing coronary artery disease (CAD) is disappointing. Considerable discussion centered on explaining why the meta-analyses failed to support the predictions derived from observational studies. IS META-ANALYSIS A VALID TECHNIQUE? The first question concerned the validity of pooling studies that have different entry criteria and different ways of collecting data. The preferred data collection method would be, through large-scale prospective trials. However, in view of economic constraints on the research community, such trials are unlikely to be undertaken in the near future. Meta-analysis was seen as the next best approach despite some problems with this method. Although mortality is the ideal end point for assessing the effects of therapy because of cost considerations, more attention must be given to surrogate end points. With meta-analysis, however, it is difficult to use surrogate end points (e.g., left ventricular mass), because these end points are not generally available in all studies. In support of meta-analysis, epidemiologists do not lump everyone together without taking account of covariants. Cross-classification is one way that epidemiologists can deal with covariants, and clinicians readily understand cross-classification. As an example, smokers and nonsmokers can be analyzed separately. Then one can separate the smokers into those with high and low cholesterol levels and further subdivide smokers with high cholesterol levels by some other variable. The limitation is that, even in a large trial, one eventually runs out of numbers. The predictions so far have been derived from two different kinds of studies, the prospective epidemiologic studies on one hand and the various clinical trials on the other. Many of the clinical trials, however, exclude important subgroups, such as insulin-dependent diabetic patients. To make progress in answering some of the questions raised at this meeting, another mechanism is needed for gathering data-one that lacks bias and is cost-effective. DOES LOWERING BLOOD PRESSURE PREVENT CORONARY ARTERY DISEASE? Lowering blood pressure probably does help to prevent CAD, even though this benefit has not met ex-
Requests for reprints should be addressed to Richard H. Grimm, Jr., M.D., University of Minnesota School of Public Health, 1912 University Avenue, Minneapolis, Minnesota 55455.
2A-245
pectations. The question remains, however, why the effect was not as great as was expected from observational studies (including the Framingham study, the Multiple Risk Factor Intervention Trial, and 15 other cohort studies). This question is particularly important in relation to “mild” hypertension, because CAD occurs at a rate three to five times higher than stroke in these “mild” hypertensive patients. It is generally agreed that when the, diastolic blood pressure is greater than 100 mm Hg, treatment is beneficial for a number of reasons, including the effect on CAD. However, the decision to treat “mild” hypertensive patients, who make up about 70% of all hypertensive patients in the United States, may depend on whether one wants to prevent coronary end points or atherosclerotic end points. Another possibility to consider is how blood pressure and other risk factors affect the end points. There could be risk factors that have an immediate acute effect, as in stroke, and others that have an antecedent effect. Atherosclerosis, for example, could have been developing for decades. Studies in adolescents and young adults have shown that hypertension begins early in life. A 50-year-old patient diagnosed as hy ertensive probably has had high blood pressure for x ecades. Therefore, is it realistic to take epidemiologic data, which are prospective, and predict how much CAD mortality could be prevented through lowering blood pressure? Consider the lag effect. Because the risk developed over many years, it may be unrealistic to expect that changing blood pressure for five years will alter the risk. Although lowering blood pressure may prevent stroke, it is probably through a different mechanism. Hypertensive patients are a remarkably heterogenous group. Grouping them according to level of blood pressure may obscure certain risk characteristics and overlook some important points concerning the future direction of the management of hypertension. It is likely that the people who experience adverse effects are different from those who benefit from treatment. It is well accepted that the interventions carry some risks and that some treatments can counteract the benefit conferred by lowering blood pressure. IS TYPE OF TREATMiNT IMPORTANT AiVD INDEPENDENT FROM EfLOOD PRESSURE REDUCTION? CAN ANTIHYPERTEVSIVE THERAPY BE INDIVIDUALIZED SO THAT PATIENTS CAN BE IDENTIFIED A PRlORl WHO WILL BENEFIT FROM SPECIFIC ANTIHYPERTENSIVE DRUGS? Traditionally, physicians have been taught that high blood pressure itself causes the risk and that normalizing blood pressure by any means removes the risk. The major trial results and the meta-analyses have challenged the concept that simply lowering blood pressure by an arbitrary number of millimeters of
February21, 1991 The AmericanJournal of Medicine Volume90 (suppl2A)
SYMPOSIUM
mercury proportionately reduces the risk of cardiovascular disease. In the 1950s clinicians had one or two antihypertensive medications to choose from. Now they have 13 classes of agents available and several more soon to come. These agents act through different mechanisms. They all lower the blood pressure effectively and predictably, but their other actions are recognized as being at least independently related ta risk. Their effect on lipid levels and on insulin resistance are among the factors that must be included in the equation for predicting benefit from blood pressure reduction. Compounding the controversy that has arisen in the last five years is that thousands of patient-years of observation have been accumulated for the diuretics, whereas ,no data are available for the angiotensinconverting enzyme (ACE) inhibitors or the calcium antagonists in terms of their effects on morbidity and mortality. Meta-analyses are legitimate but limited. Although most recent meta-analyses show a statistically signifi-
ON INSULIN &CARDIOVASCULAR
DISEASE/GRIMM
and BLACK
cant 14% reduction in fatal myoeardial infarctions, it remains far short of that predicted. The significance of the questions raised at this workshop is great because of the disease burden and cost of treatment. Trials of “mild” hypertensive patients that involve disease end points are urgently needed for newer agents such as ACE inhibitors and calcium antagonists. Although major studies would be costly, they would amount to only a fraction of the total costs of treatment. Improved methods of funding such studies, which have widespread significance and application, are needed. Studies on intermediate diseases indices, such as left ventricular mass, silent ischemia, and arrhythmias, are also necessary. To optimally individualize treatments, systematic studies must be done; when possible, these studies should be placebo-controlled. In addition, more data are needed to properly define the role of nondrug therapy in the treatment and prevention of high blood pressure. Only after these investigations are completed will we arrive at the optimal treatment of hypertension,
February 21, 1991
The American Journal of Medicine
Volume 90 (suppl 2A)
2A-25s
wo meta-analyses of antihypertensive drug trials T suggest that lowering blood pressure has a significant impact in reducing cerebrovascular complications but its effect in preventing coronary artery disease (CAD) is disappointing. Considerable discussion centered on explaining why the meta-analyses failed to support the predictions derived from observational studies. IS META-ANALYSIS A VALID TECHNIQUE? The first question concerned the validity of pooling studies that have different entry criteria and different ways of collecting data. The preferred data collection method would be, through large-scale prospective trials. However, in view of economic constraints on the research community, such trials are unlikely to be undertaken in the near future. Meta-analysis was seen as the next best approach despite some problems with this method. Although mortality is the ideal end point for assessing the effects of therapy because of cost considerations, more attention must be given to surrogate end points. With meta-analysis, however, it is difficult to use surrogate end points (e.g., left ventricular mass), because these end points are not generally available in all studies. In support of meta-analysis, epidemiologists do not lump everyone together without taking account of covariants. Cross-classification is one way that epidemiologists can deal with covariants, and clinicians readily understand cross-classification. As an example, smokers and nonsmokers can be analyzed separately. Then one can separate the smokers into those with high and low cholesterol levels and further subdivide smokers with high cholesterol levels by some other variable. The limitation is that, even in a large trial, one eventually runs out of numbers. The predictions so far have been derived from two different kinds of studies, the prospective epidemiologic studies on one hand and the various clinical trials on the other. Many of the clinical trials, however, exclude important subgroups, such as insulin-dependent diabetic patients. To make progress in answering some of the questions raised at this meeting, another mechanism is needed for gathering data-one that lacks bias and is cost-effective. DOES LOWERING BLOOD PRESSURE PREVENT CORONARY ARTERY DISEASE? Lowering blood pressure probably does help to prevent CAD, even though this benefit has not met ex-
Requests for reprints should be addressed to Richard H. Grimm, Jr., M.D., University of Minnesota School of Public Health, 1912 University Avenue, Minneapolis, Minnesota 55455.
2A-245
pectations. The question remains, however, why the effect was not as great as was expected from observational studies (including the Framingham study, the Multiple Risk Factor Intervention Trial, and 15 other cohort studies). This question is particularly important in relation to “mild” hypertension, because CAD occurs at a rate three to five times higher than stroke in these “mild” hypertensive patients. It is generally agreed that when the, diastolic blood pressure is greater than 100 mm Hg, treatment is beneficial for a number of reasons, including the effect on CAD. However, the decision to treat “mild” hypertensive patients, who make up about 70% of all hypertensive patients in the United States, may depend on whether one wants to prevent coronary end points or atherosclerotic end points. Another possibility to consider is how blood pressure and other risk factors affect the end points. There could be risk factors that have an immediate acute effect, as in stroke, and others that have an antecedent effect. Atherosclerosis, for example, could have been developing for decades. Studies in adolescents and young adults have shown that hypertension begins early in life. A 50-year-old patient diagnosed as hy ertensive probably has had high blood pressure for x ecades. Therefore, is it realistic to take epidemiologic data, which are prospective, and predict how much CAD mortality could be prevented through lowering blood pressure? Consider the lag effect. Because the risk developed over many years, it may be unrealistic to expect that changing blood pressure for five years will alter the risk. Although lowering blood pressure may prevent stroke, it is probably through a different mechanism. Hypertensive patients are a remarkably heterogenous group. Grouping them according to level of blood pressure may obscure certain risk characteristics and overlook some important points concerning the future direction of the management of hypertension. It is likely that the people who experience adverse effects are different from those who benefit from treatment. It is well accepted that the interventions carry some risks and that some treatments can counteract the benefit conferred by lowering blood pressure. IS TYPE OF TREATMiNT IMPORTANT AiVD INDEPENDENT FROM EfLOOD PRESSURE REDUCTION? CAN ANTIHYPERTEVSIVE THERAPY BE INDIVIDUALIZED SO THAT PATIENTS CAN BE IDENTIFIED A PRlORl WHO WILL BENEFIT FROM SPECIFIC ANTIHYPERTENSIVE DRUGS? Traditionally, physicians have been taught that high blood pressure itself causes the risk and that normalizing blood pressure by any means removes the risk. The major trial results and the meta-analyses have challenged the concept that simply lowering blood pressure by an arbitrary number of millimeters of
February21, 1991 The AmericanJournal of Medicine Volume90 (suppl2A)
SYMPOSIUM
mercury proportionately reduces the risk of cardiovascular disease. In the 1950s clinicians had one or two antihypertensive medications to choose from. Now they have 13 classes of agents available and several more soon to come. These agents act through different mechanisms. They all lower the blood pressure effectively and predictably, but their other actions are recognized as being at least independently related ta risk. Their effect on lipid levels and on insulin resistance are among the factors that must be included in the equation for predicting benefit from blood pressure reduction. Compounding the controversy that has arisen in the last five years is that thousands of patient-years of observation have been accumulated for the diuretics, whereas ,no data are available for the angiotensinconverting enzyme (ACE) inhibitors or the calcium antagonists in terms of their effects on morbidity and mortality. Meta-analyses are legitimate but limited. Although most recent meta-analyses show a statistically signifi-
ON INSULIN &CARDIOVASCULAR
DISEASE/GRIMM
and BLACK
cant 14% reduction in fatal myoeardial infarctions, it remains far short of that predicted. The significance of the questions raised at this workshop is great because of the disease burden and cost of treatment. Trials of “mild” hypertensive patients that involve disease end points are urgently needed for newer agents such as ACE inhibitors and calcium antagonists. Although major studies would be costly, they would amount to only a fraction of the total costs of treatment. Improved methods of funding such studies, which have widespread significance and application, are needed. Studies on intermediate diseases indices, such as left ventricular mass, silent ischemia, and arrhythmias, are also necessary. To optimally individualize treatments, systematic studies must be done; when possible, these studies should be placebo-controlled. In addition, more data are needed to properly define the role of nondrug therapy in the treatment and prevention of high blood pressure. Only after these investigations are completed will we arrive at the optimal treatment of hypertension,
February 21, 1991
The American Journal of Medicine
Volume 90 (suppl 2A)
2A-25s