Even at the time it was published, there were serious issues with AVERT. Here's our letter to the editor , published in 1999. I had actually forgotten about this letter entirely, but in retrospect, it seems pretty prescient (considering that this was published 8 years before COURAGE and 20 years before ISCHEMIA)...
Aggressive Lipid-Lowering Therapy Compared with Angioplasty in Stable Coronary Artery Disease
Published December 9, 1999
N Engl J Med 1999;341:1853-1855
DOI: 10.1056/NEJM199912093412415
To the Editor:
We would like to call attention to two critical limitations of the Atorvastatin versus Revascularization Treatment (AVERT) study (July 8 issue).1 First, we take exception to the authors' conclusion that “aggressive lowering of LDL [low-density lipoprotein] cholesterol levels . . . is at least as effective as angioplasty . . . in reducing the incidence of ischemic events in low-risk patients.” This statement implies that angioplasty is an effective means of reducing ischemic events in this target population. In fact, the results of previous controlled clinical trials suggest exactly the opposite.2,3 In the Angioplasty Compared to Medicine (ACME) trial, the six-month incidence of death, myocardial infarction, or repeated revascularization was 21 percent in the group assigned to percutaneous transluminal coronary angioplasty (PTCA) as compared with 14 percent in the medical-therapy group (relative risk, 1.5; 95 percent confidence interval, 0.9 to 2.1). Similarly, in the second Randomized Intervention Treatment of Angina (RITA-2) trial, the three-year cumulative incidence of death or nonfatal myocardial infarction was 6.3 percent in the PTCA group as compared with 3.3 percent in the medical-therapy group (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.4). The selection of a PTCA-based strategy as the control therapy in patients with minimal (if any) myocardial ischemia would thus seem to be a straw man that inherently biased the study toward a positive result for medical therapy, with or without aggressive lipid lowering.
Furthermore, the authors claim that restenosis was responsible for only a “small percentage of the events” between 6 and 18 months in the angioplasty group. Close inspection of the Kaplan–Meier curves (Figure 2 of the article), however, indicates that the main divergence in the curves occurred between six and eight months, an interval that is entirely compatible with the time course of clinical restenosis — particularly after coronary stenting. In fact, in the Stent Anticoagulation Restenosis Study,4 50 percent of the ischemic events due to restenosis occurred between 6 and 12 months after stenting. Thus, considering the known time course of coronary restenosis and in the absence of published data from an independent, core angiographic laboratory, attribution of the excess of ischemic events in the PTCA group to anything but restenosis seems highly implausible.
In summary, catheter-based percutaneous coronary intervention is a safe and effective means of controlling symptoms of ischemia in patients with one- or two-vessel disease, and aggressive lipid lowering is an effective means of stabilizing and reducing the progression of plaque. The fact that PTCA had little benefit in the AVERT study relates mainly to the selection of a patient population that had very little to gain from revascularization rather than to any specific benefit of lipid-lowering treatment. These therapies should thus be seen as additive and complementary5 rather than as mutually exclusive approaches, as the authors suggest.
David J. Cohen, M.D.
Joseph P. Carrozza, M.D.
Donald S. Baim, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
5 years ago had heart attack at an airport. Cardiac arrest during transport. CPR and defib. ROSC on arrival in ER. Quickly to Cath Lab. 2 stents. On Atorvastatin 80mg since. As a layman, I have an interest in following topics related to my specific health and I appreciate your review of this study.
I am loving these trial reviews! Quick question though: we are basically concluding that there was no difference between the 2 groups, but this is only true for the p value cut off of .045? The study reached significance for their primary endpoint of ischemic events if they had kept their original 0.05 (study had p value of .048). Also, it seems like the atorvostatin group had lower events for almost everything but just didn’t meet their p value cut off? It seems to me that saying this is a “negative trial” is a little misleading. I don’t know much about cardiology literature, but I hope they conducted a larger follow up. Also, didn’t quite understand why conducting 2 interim analyses made them drop the p value cut off?
The trial did not meet its prespecified superiority criteria. This small trial is part of the puzzle and is not conclusive given the limitations we mentioned. We will be reviewing trials of medical therapy versus revascularization in stable coronary artery disease in the next few weeks. Some of the trials we will review next are much larger and give more definite answers.
For your question about the p value - anytime we do more comparisons, we adjust the p value cut off to to ensure that the risk of false positive remains the same.
We are simply stating that this trial alone is not conclusive. This trial tested for superiority and not non-inferiority so you can't make a conclusion about non-inferiority.
We will be reviewing larger more pragmatic trials in this area next - these trials provided more conclusive answers.
When assessing treatment efficacy, we don't look at one trial but rather assess the bulk of available evidence.
Even at the time it was published, there were serious issues with AVERT. Here's our letter to the editor , published in 1999. I had actually forgotten about this letter entirely, but in retrospect, it seems pretty prescient (considering that this was published 8 years before COURAGE and 20 years before ISCHEMIA)...
Aggressive Lipid-Lowering Therapy Compared with Angioplasty in Stable Coronary Artery Disease
Published December 9, 1999
N Engl J Med 1999;341:1853-1855
DOI: 10.1056/NEJM199912093412415
To the Editor:
We would like to call attention to two critical limitations of the Atorvastatin versus Revascularization Treatment (AVERT) study (July 8 issue).1 First, we take exception to the authors' conclusion that “aggressive lowering of LDL [low-density lipoprotein] cholesterol levels . . . is at least as effective as angioplasty . . . in reducing the incidence of ischemic events in low-risk patients.” This statement implies that angioplasty is an effective means of reducing ischemic events in this target population. In fact, the results of previous controlled clinical trials suggest exactly the opposite.2,3 In the Angioplasty Compared to Medicine (ACME) trial, the six-month incidence of death, myocardial infarction, or repeated revascularization was 21 percent in the group assigned to percutaneous transluminal coronary angioplasty (PTCA) as compared with 14 percent in the medical-therapy group (relative risk, 1.5; 95 percent confidence interval, 0.9 to 2.1). Similarly, in the second Randomized Intervention Treatment of Angina (RITA-2) trial, the three-year cumulative incidence of death or nonfatal myocardial infarction was 6.3 percent in the PTCA group as compared with 3.3 percent in the medical-therapy group (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.4). The selection of a PTCA-based strategy as the control therapy in patients with minimal (if any) myocardial ischemia would thus seem to be a straw man that inherently biased the study toward a positive result for medical therapy, with or without aggressive lipid lowering.
Furthermore, the authors claim that restenosis was responsible for only a “small percentage of the events” between 6 and 18 months in the angioplasty group. Close inspection of the Kaplan–Meier curves (Figure 2 of the article), however, indicates that the main divergence in the curves occurred between six and eight months, an interval that is entirely compatible with the time course of clinical restenosis — particularly after coronary stenting. In fact, in the Stent Anticoagulation Restenosis Study,4 50 percent of the ischemic events due to restenosis occurred between 6 and 12 months after stenting. Thus, considering the known time course of coronary restenosis and in the absence of published data from an independent, core angiographic laboratory, attribution of the excess of ischemic events in the PTCA group to anything but restenosis seems highly implausible.
In summary, catheter-based percutaneous coronary intervention is a safe and effective means of controlling symptoms of ischemia in patients with one- or two-vessel disease, and aggressive lipid lowering is an effective means of stabilizing and reducing the progression of plaque. The fact that PTCA had little benefit in the AVERT study relates mainly to the selection of a patient population that had very little to gain from revascularization rather than to any specific benefit of lipid-lowering treatment. These therapies should thus be seen as additive and complementary5 rather than as mutually exclusive approaches, as the authors suggest.
David J. Cohen, M.D.
Joseph P. Carrozza, M.D.
Donald S. Baim, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
5 years ago had heart attack at an airport. Cardiac arrest during transport. CPR and defib. ROSC on arrival in ER. Quickly to Cath Lab. 2 stents. On Atorvastatin 80mg since. As a layman, I have an interest in following topics related to my specific health and I appreciate your review of this study.
I am loving these trial reviews! Quick question though: we are basically concluding that there was no difference between the 2 groups, but this is only true for the p value cut off of .045? The study reached significance for their primary endpoint of ischemic events if they had kept their original 0.05 (study had p value of .048). Also, it seems like the atorvostatin group had lower events for almost everything but just didn’t meet their p value cut off? It seems to me that saying this is a “negative trial” is a little misleading. I don’t know much about cardiology literature, but I hope they conducted a larger follow up. Also, didn’t quite understand why conducting 2 interim analyses made them drop the p value cut off?
The trial did not meet its prespecified superiority criteria. This small trial is part of the puzzle and is not conclusive given the limitations we mentioned. We will be reviewing trials of medical therapy versus revascularization in stable coronary artery disease in the next few weeks. Some of the trials we will review next are much larger and give more definite answers.
For your question about the p value - anytime we do more comparisons, we adjust the p value cut off to to ensure that the risk of false positive remains the same.
Sorry I am relatively new here. Are you arguing statins alone are inferior to PCTA?
We are simply stating that this trial alone is not conclusive. This trial tested for superiority and not non-inferiority so you can't make a conclusion about non-inferiority.
We will be reviewing larger more pragmatic trials in this area next - these trials provided more conclusive answers.
When assessing treatment efficacy, we don't look at one trial but rather assess the bulk of available evidence.
awesome! many thanks