Randomized Trials to Assess the Long-term Effects of Therapies on Angiographic End Points

Randomized Trials to Assess the Long-term Effects of Therapies on Angiographic End Points* Salim Yusuf, D.Phil.; and Reklw Garg, M.D.

(Chest 1991; 99:1243-47)

of the widespread use and safe experiences Because with coronary arteriography, investigators have attempted to use it not only as a diagnostic or prognostic tool, but also as a measure of the success of a therapy (eg, short-term efficacy of thrombolytic or adjuvant therapies in acute myocardial infarction•). In long-term studies, it has been used to study the effects of various antianginal, 2 ·3 antiplatelet, 4 and lipid10 on eoronary atheroselerosis or bylowering agents:~pass graft lesions. This eommentary is stimulated by the artiele by Loaldi et al in this issue of Chest (see pages 1238-42), and will deal with several broader issues in long-term trials in whieh angiograms are used as an end point. GENEHAL IssuEs IN TntALS WITH ANGJ<>GHAI'tllc END PotNTs

In (.'
lesions that show ehanges. All lesions within a giwn patient are subjeet to the same intervention, and their changes are in8ueneed by a eommon set of systemil· faetors (such as elevated lipids). Therefore, changes in the various lesions within a patient can be correlated with eaeh other. Additional statistieal sensitivity ean be obtained by integrating the data on eaeh lesion within a patient into a single seore per patient or hy using appropriate statistieal tests, such as elustt~r analyses. 14 However, directly l'<)mparing ehanges in lesions across groups without taking the unit of randomization (ie, the patient) into aeeount is statistieally inmrrect and (.'tmld lead to misleading eondusions. The analysis should inmrporate information from all randomized patients. In trials with dinieal t•nd points, sueh as the oecurrenee of death or infaretion, this is relatively easy to perf(mn as long as all patients are followed up. In arteriographie studit•s, the st•eond arteriogram may be unavailable heeause the patient has refused to undergo the procedure, beeaust• the study drug was stopped owing to side effects or inefficaey, because the development of major elinical events such as infarction or stroke increased the risk of the procedure, or beeause of death. Since the treatments being compared '-'
1243

Table I-Effect of Lipid Intervention on Angiographic MeaBUreB of Coronary Atherosclerosis• Change in Active Croup Relative to Control Croup, %

Active-Control Ratios

Studyt

Intervention

TC

LDL

HDL

Progression

Regression

Brensike et al• (82% of 143 during 5 yr} Blankenhorn et al7 (86% of 188 during 2 yr} Blankenhorn et al• (55% of 188 patients at 4 yrs} Brown et al• (85% of 145 during 2.5 yr} Buchwald et al• (83% of 838 at 3 yr) Buchwald et al• (75% of 838 at 5 yr} Kane et al•• (74% of97 patients at 2 yrs)

Ch

-16

-21

+6

32149 (.65}

7n {1.0}

N+C

-22

-38

+35

39/61 (.64)

1612 (8.0}

N+C

-21

-34

+35

45175 (.60)

1816 (3.0}

L+C N+C P1B

-31 -20

-39 -38f

+10 +38 +4f

21146 (.46} 25/46 (.54) 28141 (.68}

31/ll (2.8) 39/ll (3.5} 9/7 (1.3}

PIB

-23

-38

+4

38165 (.58}

1215 (2.4}

N+C

-22

-29

+16

20/41 (.49}

33113 (2.6}

-25:t

-25

*Abbreviations: Ch=cholestyramine; N=niacin; C=colestipol; L=lovastatin; PIB=partial ileal bypass; TC=total cholesterol; LDL=Iowdensity lipoprotein cholesterol; HDL= high-density lipoprotein cholesterol. tData in parentheses indicate proportion of patients for whom both baseline and subsequent angiograms were available. The study by Ornish et al 13 was excluded because of the high proportion of randomized patients for whom angiographic data were unavailable (53194}; it was considered that the results might therefore be substantially confounded or biased. fValues are extrapolations from 1- and 5-yr values provided in that study.

studies or from data demonstrating similar changes in independent, but medically related, end points (eg, if a decrease in the rate of development of atherosclerosis is observed, this claim is more plausible if accompanied by similar changes in related clinical end points, such as angina or infarction). ANGIOGRAPHIC STUDIES WITH MoDIFICATION OF LIPIDS

There have been at least six randomized trials comparing the effects of modulating lipid levels.:s- 10 •15 One study1 5 is seriously flawed because it included only a minority of the patients randomized. Significant biases might have arisen in the types of patients who were selected or who volunteered to undergo repeat angiography. Further potential flaws in blinding could confound the arteriographic analyses. The other five studies were much more rigorous in their approach (Table 1).:s- 10 Although none of these studies included all randomized patients in the analysis, second arteriograms were available in a high proportion of patients. In all five studies, significant reductions in lowdensity lipoprotein {LDL) cholesterol were achieved {range, - 21 percent to -46 percent). In three studies that used nicotinic acid,7·9 •10 there were marked elevations in high-density lipoprotein (HDL) cholesterol ( +28 percent, + 42 percent and + 16 percent) and reductions in triglycerides (- 19 percent, - 30 percent and - 29 percent). The rates of progression of atherosclerosis were so markedly different between the treatment and control groups and the levels of statistical significance were so extreme, that potential biases due to missing data or extrapolation of missing 1244

values are unlikely to have altered the main conclusion of any of the studies. Of particular note, four of these trials 7• 10 also reported a higher incidence of regression in existing atherosclerotic lesions among actively treated patients compared with controls. One might hypothesize from these trials that progression of atherosclerosis can be prevented by even moderate reductions in LDL cholesterol (eg, Brensike et al6 ), but that more marked reductions in LDL cholesterol, especially ifaccompanied by elevations in HDL cholesterol, could lead to more marked benefit or even regression of existing lesions within two years. This is a relatively short period compared to the decades during which the lesions develop in middle-aged persons. In the study by Buchwald et al, 5 serial arteriograms were obtained at three, five, seven, and ten years. The data suggest that the differences between the active and control groups were more marked at five years than at three years. However, the differences at seven years and ten years were similar to those seen at five years, indicating that reduction in LDL cholesterol might exert its full effect on retarding atherosclerosis by about five years. 5 Given the fairly high proportion of patients with missing arteriograms at seven and ten years, this observation should be cautiously interpreted, unless confirmed by future studies. ANGIOGRAPHIC STUDIES WITH ANTIPLATELET AGENTS

There have been several trials of the effect of antiplatelet agents in preventing early closure of saphenous vein grafts following coronary artery bypass Assessing Effecls of Therapies on Angiographlc End Points {'llisuf, Garg)

the effects of various agents used for reducing blood pressure or relieving angina have become available (Table 2). In two trials, the effect of a calcium antagonist was compared to placebo over a two-year period. There was no effect in either trial on progression or regression of existing lesions. Although both trials claimed to demonstrate a reduction in the development of new lesions, these claims should be critically examined. In the study by Lichtlen et al, 2 103 new lesions occurred in the nifedipine group in 70 patients, compared with 144 among 85 patients in the placebo group. Comparison of the proportion of patients in whom new lesions developed (70 vs 85) does not reach conventional levels of statistical significance (onetailed p = 0.129). Although a comparison of the numbers of lesions that developed (103 vs 144) appears to be nominally significant (one-tailed p = 0.034), such an analysis may not be appropriate as discussed earlier in this article (patients, not lesions, were randomized). Moreover, a large number of statistical tests were conducted, and it is not clear whether these analyses were specified prior to examining the data. The number of patients in whom side effects developed was substantially greater in the nifedipine group. Of particular concern, there were 12 deaths (5. 7 percent) among the patients allocated to receive nifedipine, compared with two (0.9 percent) in the placebo group (p=0.02). In the study by Waters et al, 3 new lesions developed in fewer patients in the group treated with nicardipine than in the placebo group (12 percent vs 24 percent) in a subset of patients (217/383) who had only minimal lesions on the baseline angiogram. Although this difference was nominally significant (p =0.035), the authors were careful to point out that this was a post hoc subgroup analysis, that numerous statistical tests were performed in their study, and that firm concluANGIOGRAPHIC STUDIES WITH sions would require confirmatory data from independANTIANGINALIANTIHYPERTENSIVE AGENTS ent studies. There were two deaths and 14 patients In the past year, three randomized trials evaluating suffered myocardial infarction in the group allocated Table 2-E.ffects of Calcium-Channel Blockers or Beta-Blockers on Coronary Atherosclerosis

graft surgery. 4 The data from the various trials conclusively demonstrate a reduction in saphenous vein graft occlusion. Most of these studies were of only a few months' duration and were therefore too short to evaluate the effects of antiplatelet therapy on native coronary atherosclerosis. 4 Several small studies have examined the effects of various antiplatelet regimens in preventing reocclusion or restenosis following percutaneous transluminal coronary angioplasty. 16 In most of these studies repeat angiograms were not available for all randomized patients. Moreover, the patients who underwent the repeat angiography were a highly selected subset and may overrepresent those with recurrent angina or infarction. In such circumstances, the results are extremely difficult to interpret. Ohman et al 17 reviewed these trials and concluded that antiplatelet agents may reduce the risk of restenosis by about 20 percent, if the data that were missing were not biased. However, the numbers of patients studied were limited; consequently, the 95 percent confidence intervals are wide, and the observed difference is not statistically significant (odds ratio of 0.81, 95 percent confidence interval of 0.57 to 1.14 for aspirin vs no treatment; odds ratio of 0.86, 95 percent confidence interval of 0.50 to 1.46 for low-dose vs high-dose aspirin). There have been two randomized trials of ticlopidine; one showed a favorable but nonsignificant difference, and the other showed no effect. 16 The study by Chesebro et aJlH of prolonged treatment for five years, confirmed that aspirin prevented vascular (coronary) occlusion but did not affect the rate of progression of existing nonocclusive lesions. However, there were significantly fewer treated patients in whom new lesions developed at sites that were apparently normal on the initial arteriogram compared to the control group.

Study*

Drugs

Lichtlen et aP

Nifedipine vs placebo Nicardipine vs placebo Propranolol vs isosorhide dinitrate

Waters et al' Loaldi et al

Progression of Existing Lesionst

Development of New Lesionst

No. of Randomized Patients

Proportion of P.atien ts with Angiograms, %

Active

Control

Active

Control

425

82

431173 (25)

391175 (22)

70/173 (40)

85/175 (49)

383

87

92/168 (55)

951167 (57)

15199 (15)

32/118 (27)*

80

100

28/40 (70)

19140 (48)*

NA

NA

*The study by Gottlieb et al" is not included because follow-up data were available for only 64/144 (44%) patients who had been randomized. tValues are ratios of affected and unaffected patients in active and control groups, with percentages in parentheses. NA =not available. In the study by Waters et al, only 217 patients who had minimal lesions at baseline were included in the analysis of development of new lesions. *Comparison significant at p<0.05. All other <.·omparisons are not statistically significant. CHEST I 99 I 5 I MAY. 1991

1245

to receive nicardipine, compared with three and eight, respectively, in the placebo group. There were no differences in the numbers of patients in whom angina worsened in either the study by Lichtlen et aJ2 or that by Waters et aJ.3 The data from both studies are consistent and together indicate no effect of this class of calcium antagonists on pro1-,rression or regression of existing <.·oronary atherosclerosis, although there is a suggestion that the development of new lesions may be prevented. However, there appears to be little effect on prevention of worsening angina and perhaps an adverse effect on mortality and infarction. The latter effect is consistent with the results of several trials of nifedipine in patients with unstable angina and myocardial infarction, indicating a tendency toward a higher mortality and reinfarction rate. 21 In this issue, Loaldi et al describe their experience with 80 patients with angina pectoris randomized to receive propranolol or isosorbide dinitrate for two years. The authors chose to use nitrates in one group because of the lack of any study indicating that these agents interfere with the atherosclerotic process. Therefore, they considered patients randomized to this group as representing a placebo group. The proportion of patients with progression of atherosclerosis was significantly (p<0.05) greater in the propranolol group than in the nitrate group. Whether this difference is due to an adverse effect of propranolol or to a beneficial effect of nitrates 21 (eg, by increasing the level of endothelium-derived relaxation factor or by preventing platelet aggregation) cannot be ascertained from this study. However, a significant decrease in HDL cholesterol (- 31 percent) and increase in triglycerides ( + 23 percent) in the propranolol group raises the possibility that propranolol may have an adverse effect on atherosclerosis. Similar directional changes in lipids have been reported in several previous studies ofbeta-blockers. 22 However, in the large Beta-Blocker Heart Attack Trial, the differences in HDL cholesterol and triglycerides after one year of treatment between the propranolol and placebo groups was much more modest (HDL was lower by about 7 percent and triglycerides were higher by about 14.5 percent). 23 This suggests that the larger differences in lipids observed by Loaldi et al might be due either to chance or to some hitherto unknown beneficial effect of nitrates. The apparent adverse effects of beta-blockers on atherosclerosis observed by L>aldi et al contrast with the voluminous data demonstrating a clear and significant decrease in mortality and recurrent infarction with beta-blockers in the acute and late phases of myocardial infarction. 24 In addition, there are some data that suggest that beta-blockers may reduce the risk of infarction in hypertensive patients. :z.~ These 1246

arguments support the possibility that nitrates may have a beneficial effect on progression of atherosclerosis. The apparent contradictions in the effects of propranolol and calcium antagonists on atherosclerosis compared with their effects on death and infarction raise several possibilities: 1. Correlation between progression of coronary atherosclerosis and clinical events may be only modest. This suggestion is supported by various studies that indicate that, although the presence of coronary lesions may be related to a subsequent outcome, the correlation between severity of lesion and risk of infarction may not be clear. A lesion that is only moderately stenosed may ulcerate or dissect, and this may lead to the development of coronary thrombus and infarction. 26 2. Although progression of coronary disease increases the risk of a subsequent infarction, betablockers may prevent infarction by other mechanisms (eg, by lowering plaque stress through reduction in heart rate and peak systolic pressure); these effects may lead to a decrease in plaque dissection and rupture. This hypothesis is similar to parallel observations from randomized trials indicating a reduction in cardiac rupture and aortic dissection with betablockers in acute infarction. 27 The trend toward an adverse effect on infarction or death observed with the dihydropyridine calcium antagonists in several trials of myocardial infarction, unstable angina, and stable angina may be explained by some unidentified harmful effect that outweighs the benefits of blood pressure reduction, decrease in oxygen consumption, prevention of calcium overload of cells, and other variables. For example, the reflex tachycardia induced by these agents may increase the risk of plaque dissection and rupture, thereby increasing coronary occlusion and myocardial infarction. 3. The differences in lipid levels and atherosclerosis progression between the propranolol and nitrate groups observed by Loaldi et al may be due to a combination of a beneficial effect of nitrates and a small adverse effect of propranolol. Therefore, future studies comparing propranolol and nitrates with a placebo are needed. In patients with angina pectoris, utilization of a placebo on a long-term basis may be difficult. An alternative design to clarify the relative effect of each of these agents might be by randomizing patients to propranolol alone (group A), nitrate alone (group B), or propranolol plus nitrates (group C). Comparison of groups A and C will clarify the value of nitrates, and comparison of groups B and C will clarify the value of propranolol (assuming that there is no major interaction of effects). Regardless of the validity of any of the above hypotheses, the decision whether to prefer a specific Assessing Effects of Therapies on Angiographic End Points (Yusuf, Garg)

agent should be based on the net value of a particular therapy on the benefit-risk equation on clinical end points. While effects on surrogate end points, such as progression of atherosclerosis, may provide leads to mechanisms and may be used in support of other clinical data, it would be premature at present to use information from such trials to replace studies in which direct evidence of effects on clinical end points is sought. Several moderate-sized studies comparing different antianginal or antihypertensive drugs are being conducted. Larger studies on some thousands of patients followed up for a few years are critical to clarify the relative clinical merits of the various classes of antianginal and antihypertensive agents. ACKNOWLEDGMENT: We thank Zola Hall li:>r typing this manuscript.

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