Prakash Deedwania

Because cardiovascular deaths account for 65%–70% of deaths in patients with diabetes, the disease has been labeled by various guideline committees as a coronary heart disease risk equivalent. Although there has been some debate regarding this, the recent data from a meta-analysis of 102 prospective studies with 8.49 million person-years of follow-up – showing that diabetes confers a twofold excess risk for CHD, major strokes, and deaths attributable to other vascular diseases – leaves little room for discussion in this regard (Lancet 2010;375:2215–22).

The vast majority of national and international guidelines have recommended aggressive management strategies to reduce blood glucose, blood pressure, and lipids in patients with diabetes in the hope of reducing CV events, despite the paucity of data from well-designed, prospective, randomized, controlled trials (RCTs). However, during the past decade, several well-designed RCTs have examined and compared the role of intensive versus usual management strategies in reducing the risk of macrovascular and microvascular events in DM. These studies include the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT).

Results from all of these well-designed RCTs have been somewhat perplexing, and contrary to the prevailing concepts. First of all, the results from the intensive glucose control arm from all three trials showed that the intensive glucose control strategy was not only associated with lack of benefit in primary end point, but indeed was harmful in a certain subset of patients due to the risks associated with resultant hypoglycemia. The results of the ACCORD study are particularly important because there was increased mortality in the ACCORD intensive glycemic control arm, which persisted even 1.5 years after the therapy for intensive control of glucose was stopped. The risk of hypoglycemia is further emphasized by the recent presentation from the ADVANCE group in showing that severe symptomatic hypoglycemia was associated with nearly threefold increased risks of macrovascular events, cardiovascular mortality, and all-cause mortality (N. Engl. J. Med. 2010;363:1410–8).

The lack of benefit of an intensive glucose control strategy should not be entirely surprising, because the prevailing wisdom was based on epidemiologic data showing higher risk of CV events with higher levels of glucose. However, it is important to realize that such an association might be due to other risks and/or risk factors. For now, based on the totality of the data it seems appropriate to be not too aggressive in controlling blood glucose and to stick with the current target of HbA_1C below 7% for most patients with diabetes.

The lack of benefits reported from the ACCORD and ADVANCE blood pressure arms of the studies also deserves mention. In ACCORD, intensive antihypertensive therapy was targeted to a systolic pressure of less than 120 mm Hg and standard therapy treated to a systolic pressure target of less than 140 mm Hg. After 1 year, the mean systolic BP was 119 mm Hg in the intensive therapy group and 134 mm Hg in the standard-therapy group. At 1 year there was no difference in the primary composite outcome (nonfatal MI, nonfatal stroke, or death from cardiovascular causes).

It should perhaps not come as a surprise that there was no improvement in the primary composite outcome, since control of BP to less than 130 mm Hg systolic has not been shown to improve coronary events in most studies. On the other hand, there has been a close correlation between systolic BP and risk of stroke rate down to a lower value of 115 mm Hg, and in the ACCORD BP study also it was shown that decreasing systolic BP to a mean value of 119 mm Hg was associated with a 41% decrease in all stroke and also a significant reduction in nonfatal strokes.

Results from the ADVANCE study are also instructive in the management of hypertension in the diabetic patient. Compared with patients assigned placebo, those who received active therapy had a mean reduction in systolic BP of 5.6 mm Hg (mean 135 mm Hg in the active group vs. 140 mg Hg with placebo) and diastolic blood pressure of 2.2 mm Hg (mean 75 mm Hg and 77 mm Hg, respectively). The relative risk of death from cardiovascular disease was reduced by 18%, and death from any cause was reduced by 14%, both significant differences. This benefit was attributed mostly to reduction in microvascular events. Thus, unlike the aggressive glucose arms of the studies it appears that the BP control strategy does work and reduces the macrovascular end points directly related to BP.

Based on these results, it is fair to conclude that the evidence supports a comprehensive risk-reduction strategy addressing most risk factors in diabetes. However, such a strategy should include consideration of possible hazards of aggressive therapy. As always, the benefit:risk ratio should be carefully evaluated for each individual patient. We should remember the old maxim and Hippocratic oath, that above all we should do no harm.

Because cardiovascular deaths account for 65%–70% of deaths in patients with diabetes, the disease has been labeled by various guideline committees as a coronary heart disease risk equivalent. Although there has been some debate regarding this, the recent data from a meta-analysis of 102 prospective studies with 8.49 million person-years of follow-up – showing that diabetes confers a twofold excess risk for CHD, major strokes, and deaths attributable to other vascular diseases – leaves little room for discussion in this regard (Lancet 2010;375:2215–22).

The vast majority of national and international guidelines have recommended aggressive management strategies to reduce blood glucose, blood pressure, and lipids in patients with diabetes in the hope of reducing CV events, despite the paucity of data from well-designed, prospective, randomized, controlled trials (RCTs). However, during the past decade, several well-designed RCTs have examined and compared the role of intensive versus usual management strategies in reducing the risk of macrovascular and microvascular events in DM. These studies include the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT).

Results from all of these well-designed RCTs have been somewhat perplexing, and contrary to the prevailing concepts. First of all, the results from the intensive glucose control arm from all three trials showed that the intensive glucose control strategy was not only associated with lack of benefit in primary end point, but indeed was harmful in a certain subset of patients due to the risks associated with resultant hypoglycemia. The results of the ACCORD study are particularly important because there was increased mortality in the ACCORD intensive glycemic control arm, which persisted even 1.5 years after the therapy for intensive control of glucose was stopped. The risk of hypoglycemia is further emphasized by the recent presentation from the ADVANCE group in showing that severe symptomatic hypoglycemia was associated with nearly threefold increased risks of macrovascular events, cardiovascular mortality, and all-cause mortality (N. Engl. J. Med. 2010;363:1410–8).

The lack of benefit of an intensive glucose control strategy should not be entirely surprising, because the prevailing wisdom was based on epidemiologic data showing higher risk of CV events with higher levels of glucose. However, it is important to realize that such an association might be due to other risks and/or risk factors. For now, based on the totality of the data it seems appropriate to be not too aggressive in controlling blood glucose and to stick with the current target of HbA_1C below 7% for most patients with diabetes.

The lack of benefits reported from the ACCORD and ADVANCE blood pressure arms of the studies also deserves mention. In ACCORD, intensive antihypertensive therapy was targeted to a systolic pressure of less than 120 mm Hg and standard therapy treated to a systolic pressure target of less than 140 mm Hg. After 1 year, the mean systolic BP was 119 mm Hg in the intensive therapy group and 134 mm Hg in the standard-therapy group. At 1 year there was no difference in the primary composite outcome (nonfatal MI, nonfatal stroke, or death from cardiovascular causes).

It should perhaps not come as a surprise that there was no improvement in the primary composite outcome, since control of BP to less than 130 mm Hg systolic has not been shown to improve coronary events in most studies. On the other hand, there has been a close correlation between systolic BP and risk of stroke rate down to a lower value of 115 mm Hg, and in the ACCORD BP study also it was shown that decreasing systolic BP to a mean value of 119 mm Hg was associated with a 41% decrease in all stroke and also a significant reduction in nonfatal strokes.

Results from the ADVANCE study are also instructive in the management of hypertension in the diabetic patient. Compared with patients assigned placebo, those who received active therapy had a mean reduction in systolic BP of 5.6 mm Hg (mean 135 mm Hg in the active group vs. 140 mg Hg with placebo) and diastolic blood pressure of 2.2 mm Hg (mean 75 mm Hg and 77 mm Hg, respectively). The relative risk of death from cardiovascular disease was reduced by 18%, and death from any cause was reduced by 14%, both significant differences. This benefit was attributed mostly to reduction in microvascular events. Thus, unlike the aggressive glucose arms of the studies it appears that the BP control strategy does work and reduces the macrovascular end points directly related to BP.

Based on these results, it is fair to conclude that the evidence supports a comprehensive risk-reduction strategy addressing most risk factors in diabetes. However, such a strategy should include consideration of possible hazards of aggressive therapy. As always, the benefit:risk ratio should be carefully evaluated for each individual patient. We should remember the old maxim and Hippocratic oath, that above all we should do no harm.

Because cardiovascular deaths account for 65%–70% of deaths in patients with diabetes, the disease has been labeled by various guideline committees as a coronary heart disease risk equivalent. Although there has been some debate regarding this, the recent data from a meta-analysis of 102 prospective studies with 8.49 million person-years of follow-up – showing that diabetes confers a twofold excess risk for CHD, major strokes, and deaths attributable to other vascular diseases – leaves little room for discussion in this regard (Lancet 2010;375:2215–22).

The vast majority of national and international guidelines have recommended aggressive management strategies to reduce blood glucose, blood pressure, and lipids in patients with diabetes in the hope of reducing CV events, despite the paucity of data from well-designed, prospective, randomized, controlled trials (RCTs). However, during the past decade, several well-designed RCTs have examined and compared the role of intensive versus usual management strategies in reducing the risk of macrovascular and microvascular events in DM. These studies include the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT).

Results from all of these well-designed RCTs have been somewhat perplexing, and contrary to the prevailing concepts. First of all, the results from the intensive glucose control arm from all three trials showed that the intensive glucose control strategy was not only associated with lack of benefit in primary end point, but indeed was harmful in a certain subset of patients due to the risks associated with resultant hypoglycemia. The results of the ACCORD study are particularly important because there was increased mortality in the ACCORD intensive glycemic control arm, which persisted even 1.5 years after the therapy for intensive control of glucose was stopped. The risk of hypoglycemia is further emphasized by the recent presentation from the ADVANCE group in showing that severe symptomatic hypoglycemia was associated with nearly threefold increased risks of macrovascular events, cardiovascular mortality, and all-cause mortality (N. Engl. J. Med. 2010;363:1410–8).

The lack of benefit of an intensive glucose control strategy should not be entirely surprising, because the prevailing wisdom was based on epidemiologic data showing higher risk of CV events with higher levels of glucose. However, it is important to realize that such an association might be due to other risks and/or risk factors. For now, based on the totality of the data it seems appropriate to be not too aggressive in controlling blood glucose and to stick with the current target of HbA_1C below 7% for most patients with diabetes.

The lack of benefits reported from the ACCORD and ADVANCE blood pressure arms of the studies also deserves mention. In ACCORD, intensive antihypertensive therapy was targeted to a systolic pressure of less than 120 mm Hg and standard therapy treated to a systolic pressure target of less than 140 mm Hg. After 1 year, the mean systolic BP was 119 mm Hg in the intensive therapy group and 134 mm Hg in the standard-therapy group. At 1 year there was no difference in the primary composite outcome (nonfatal MI, nonfatal stroke, or death from cardiovascular causes).

It should perhaps not come as a surprise that there was no improvement in the primary composite outcome, since control of BP to less than 130 mm Hg systolic has not been shown to improve coronary events in most studies. On the other hand, there has been a close correlation between systolic BP and risk of stroke rate down to a lower value of 115 mm Hg, and in the ACCORD BP study also it was shown that decreasing systolic BP to a mean value of 119 mm Hg was associated with a 41% decrease in all stroke and also a significant reduction in nonfatal strokes.

Results from the ADVANCE study are also instructive in the management of hypertension in the diabetic patient. Compared with patients assigned placebo, those who received active therapy had a mean reduction in systolic BP of 5.6 mm Hg (mean 135 mm Hg in the active group vs. 140 mg Hg with placebo) and diastolic blood pressure of 2.2 mm Hg (mean 75 mm Hg and 77 mm Hg, respectively). The relative risk of death from cardiovascular disease was reduced by 18%, and death from any cause was reduced by 14%, both significant differences. This benefit was attributed mostly to reduction in microvascular events. Thus, unlike the aggressive glucose arms of the studies it appears that the BP control strategy does work and reduces the macrovascular end points directly related to BP.

Based on these results, it is fair to conclude that the evidence supports a comprehensive risk-reduction strategy addressing most risk factors in diabetes. However, such a strategy should include consideration of possible hazards of aggressive therapy. As always, the benefit:risk ratio should be carefully evaluated for each individual patient. We should remember the old maxim and Hippocratic oath, that above all we should do no harm.

Has PEACE ever before caused such havoc?

The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial has been widely misinterpreted, to the detriment of patient care.

PEACE involved the double-blind randomization of patients with stable coronary artery disease (CAD) and normal left ventricular systolic function to the ACE inhibitor trandolapril or placebo on top of modern conventional therapy with other drugs of proven effectiveness. Surprisingly, the trandolapril group experienced no reduction in clinical atherosclerotic events, compared with placebo. Many physicians have concluded as a result that the study casts doubt upon the overall vasculoprotective effects of ACE inhibition.

So what effect, then, has PEACE had on my own clinical practice? None whatsoever. I continue to place essentially all my patients with CAD or any other form of vascular disease and normal left ventricular systolic function on an ACE inhibitor, giving preference to those agents that have demonstrated compelling evidence of benefit in this setting—namely, ramipril and perindopril. And in talking with cardiology opinion leaders, I find most of them are doing the same.

Why are many of us not more willing to give PEACE a chance? Because the persuasive bulk of the randomized clinical trial data, including the nearly 10,000-patient Heart Outcomes Prevention Evaluation (HOPE) trial as well as the 12,218-patient European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), has shown that ACE inhibitor therapy results in a highly significant 20%-22% reduction in atherosclerotic events in patients with CAD or other vascular disease but no history of heart failure or depressed left ventricular systolic function.

This demonstrated clinical efficacy has a compelling mechanistic basis. ACE inhibitors not only lower blood pressure, they also have antithrombotic properties, have antioxidant effects, potentiate bradykinin, reduce vascular inflammation, promote atherosclerotic plaque stabilization, reduce endothelial dysfunction, and curb deleterious vascular and cardiac remodeling. It's a very potent package of beneficial effects.

PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function randomized at 187 U.S., Canadian, and Italian sites to trandolapril at a target dose of 4 mg/day or placebo. After a median 4.8-year follow-up, the incidence of the primary study end point—a composite of cardiovascular death, acute myocardial infarction, or coronary revascularization—was 21.9% in the trandolapril arm and 22.5% with placebo. Nearly identical. There were no identifiable patient subgroups that benefited from the ACE inhibitor.

Why did the outcome of PEACE differ so from those of HOPE and EUROPA? One possibility is that not all ACE inhibitors are equally effective in patients like those included in these three studies. Perhaps trandolapril, unlike ramipril and perindopril, simply doesn't cut the mustard in this setting. Maybe a more lipophilic ACE inhibitor is required. This, in my view, is an unlikely explanation.

It is much more likely that the difference in PEACE was due to the markedly higher background utilization rates of other drugs of proven effectiveness in vasculopathic patients. To put it plainly, because of changing practice patterns, the patients were much better treated in terms of guideline-recommended therapies for their coexisting risk factors. The use of statins, for example, was significantly more common in PEACE than in the earlier HOPE and EUROPA trials. The PEACE participants on statin therapy were also treated to lower target LDL-cholesterol values.

Similarly, PEACE participants had higher rates of antiplatelet therapy than those in HOPE and EUROPA. They also had better blood pressure control, greater utilization of β-blocker therapy, and a higher rate of coronary revascularization procedures prior to study enrollment.

PEACE has raised an important question in my mind and in those of other observers: If we treat our patients in exemplary fashion with all of the other guideline-recommended risk-reduction therapies, do we still obtain added value from ACE inhibitor therapy, or does it become redundant? The verdict is still out on that. But because the weight of the evidence to date still supports the vasculoprotective role of ACE inhibitors, I'm not planning to change my own practice unless a future randomized trial replicates the PEACE findings.

I don't expect that to happen. In fact, that kind of a trial will be virtually impossible to conduct. It would be a no-win situation for a sponsoring pharmaceutical company, and the National Institutes of Health usually does not conduct comparative trials.

Has PEACE ever before caused such havoc?

The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial has been widely misinterpreted, to the detriment of patient care.

PEACE involved the double-blind randomization of patients with stable coronary artery disease (CAD) and normal left ventricular systolic function to the ACE inhibitor trandolapril or placebo on top of modern conventional therapy with other drugs of proven effectiveness. Surprisingly, the trandolapril group experienced no reduction in clinical atherosclerotic events, compared with placebo. Many physicians have concluded as a result that the study casts doubt upon the overall vasculoprotective effects of ACE inhibition.

So what effect, then, has PEACE had on my own clinical practice? None whatsoever. I continue to place essentially all my patients with CAD or any other form of vascular disease and normal left ventricular systolic function on an ACE inhibitor, giving preference to those agents that have demonstrated compelling evidence of benefit in this setting—namely, ramipril and perindopril. And in talking with cardiology opinion leaders, I find most of them are doing the same.

Why are many of us not more willing to give PEACE a chance? Because the persuasive bulk of the randomized clinical trial data, including the nearly 10,000-patient Heart Outcomes Prevention Evaluation (HOPE) trial as well as the 12,218-patient European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), has shown that ACE inhibitor therapy results in a highly significant 20%-22% reduction in atherosclerotic events in patients with CAD or other vascular disease but no history of heart failure or depressed left ventricular systolic function.

This demonstrated clinical efficacy has a compelling mechanistic basis. ACE inhibitors not only lower blood pressure, they also have antithrombotic properties, have antioxidant effects, potentiate bradykinin, reduce vascular inflammation, promote atherosclerotic plaque stabilization, reduce endothelial dysfunction, and curb deleterious vascular and cardiac remodeling. It's a very potent package of beneficial effects.

PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function randomized at 187 U.S., Canadian, and Italian sites to trandolapril at a target dose of 4 mg/day or placebo. After a median 4.8-year follow-up, the incidence of the primary study end point—a composite of cardiovascular death, acute myocardial infarction, or coronary revascularization—was 21.9% in the trandolapril arm and 22.5% with placebo. Nearly identical. There were no identifiable patient subgroups that benefited from the ACE inhibitor.

Why did the outcome of PEACE differ so from those of HOPE and EUROPA? One possibility is that not all ACE inhibitors are equally effective in patients like those included in these three studies. Perhaps trandolapril, unlike ramipril and perindopril, simply doesn't cut the mustard in this setting. Maybe a more lipophilic ACE inhibitor is required. This, in my view, is an unlikely explanation.

It is much more likely that the difference in PEACE was due to the markedly higher background utilization rates of other drugs of proven effectiveness in vasculopathic patients. To put it plainly, because of changing practice patterns, the patients were much better treated in terms of guideline-recommended therapies for their coexisting risk factors. The use of statins, for example, was significantly more common in PEACE than in the earlier HOPE and EUROPA trials. The PEACE participants on statin therapy were also treated to lower target LDL-cholesterol values.

Similarly, PEACE participants had higher rates of antiplatelet therapy than those in HOPE and EUROPA. They also had better blood pressure control, greater utilization of β-blocker therapy, and a higher rate of coronary revascularization procedures prior to study enrollment.

PEACE has raised an important question in my mind and in those of other observers: If we treat our patients in exemplary fashion with all of the other guideline-recommended risk-reduction therapies, do we still obtain added value from ACE inhibitor therapy, or does it become redundant? The verdict is still out on that. But because the weight of the evidence to date still supports the vasculoprotective role of ACE inhibitors, I'm not planning to change my own practice unless a future randomized trial replicates the PEACE findings.

I don't expect that to happen. In fact, that kind of a trial will be virtually impossible to conduct. It would be a no-win situation for a sponsoring pharmaceutical company, and the National Institutes of Health usually does not conduct comparative trials.

Has PEACE ever before caused such havoc?

The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial has been widely misinterpreted, to the detriment of patient care.

PEACE involved the double-blind randomization of patients with stable coronary artery disease (CAD) and normal left ventricular systolic function to the ACE inhibitor trandolapril or placebo on top of modern conventional therapy with other drugs of proven effectiveness. Surprisingly, the trandolapril group experienced no reduction in clinical atherosclerotic events, compared with placebo. Many physicians have concluded as a result that the study casts doubt upon the overall vasculoprotective effects of ACE inhibition.

So what effect, then, has PEACE had on my own clinical practice? None whatsoever. I continue to place essentially all my patients with CAD or any other form of vascular disease and normal left ventricular systolic function on an ACE inhibitor, giving preference to those agents that have demonstrated compelling evidence of benefit in this setting—namely, ramipril and perindopril. And in talking with cardiology opinion leaders, I find most of them are doing the same.

Why are many of us not more willing to give PEACE a chance? Because the persuasive bulk of the randomized clinical trial data, including the nearly 10,000-patient Heart Outcomes Prevention Evaluation (HOPE) trial as well as the 12,218-patient European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), has shown that ACE inhibitor therapy results in a highly significant 20%-22% reduction in atherosclerotic events in patients with CAD or other vascular disease but no history of heart failure or depressed left ventricular systolic function.

This demonstrated clinical efficacy has a compelling mechanistic basis. ACE inhibitors not only lower blood pressure, they also have antithrombotic properties, have antioxidant effects, potentiate bradykinin, reduce vascular inflammation, promote atherosclerotic plaque stabilization, reduce endothelial dysfunction, and curb deleterious vascular and cardiac remodeling. It's a very potent package of beneficial effects.

PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function randomized at 187 U.S., Canadian, and Italian sites to trandolapril at a target dose of 4 mg/day or placebo. After a median 4.8-year follow-up, the incidence of the primary study end point—a composite of cardiovascular death, acute myocardial infarction, or coronary revascularization—was 21.9% in the trandolapril arm and 22.5% with placebo. Nearly identical. There were no identifiable patient subgroups that benefited from the ACE inhibitor.

Why did the outcome of PEACE differ so from those of HOPE and EUROPA? One possibility is that not all ACE inhibitors are equally effective in patients like those included in these three studies. Perhaps trandolapril, unlike ramipril and perindopril, simply doesn't cut the mustard in this setting. Maybe a more lipophilic ACE inhibitor is required. This, in my view, is an unlikely explanation.

It is much more likely that the difference in PEACE was due to the markedly higher background utilization rates of other drugs of proven effectiveness in vasculopathic patients. To put it plainly, because of changing practice patterns, the patients were much better treated in terms of guideline-recommended therapies for their coexisting risk factors. The use of statins, for example, was significantly more common in PEACE than in the earlier HOPE and EUROPA trials. The PEACE participants on statin therapy were also treated to lower target LDL-cholesterol values.

Similarly, PEACE participants had higher rates of antiplatelet therapy than those in HOPE and EUROPA. They also had better blood pressure control, greater utilization of β-blocker therapy, and a higher rate of coronary revascularization procedures prior to study enrollment.

PEACE has raised an important question in my mind and in those of other observers: If we treat our patients in exemplary fashion with all of the other guideline-recommended risk-reduction therapies, do we still obtain added value from ACE inhibitor therapy, or does it become redundant? The verdict is still out on that. But because the weight of the evidence to date still supports the vasculoprotective role of ACE inhibitors, I'm not planning to change my own practice unless a future randomized trial replicates the PEACE findings.

I don't expect that to happen. In fact, that kind of a trial will be virtually impossible to conduct. It would be a no-win situation for a sponsoring pharmaceutical company, and the National Institutes of Health usually does not conduct comparative trials.