The sound bites about these trials in the news have confused physicians and patients alike. But, as we have all experienced during this election year, to understand complex problems requires an in-depth analysis instead of a sound bite.

I was troubled by the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,² in which more patients who were treated with an intense hemoglobin A_1c-lowering strategy died (mostly of macrovascular events) than those treated with a standard strategy. Older data showing a beneficial effect of glucose-lowering on the microvascular complications of diabetes are solid. I did not understand the mechanistic basis of the ACCORD results, unless the very aggressive therapy caused many hypoglycemic events with catecholamine surges, resulting in stroke or myocardial infarction, or whether a problem with a specific drug arose more often in the intensive-treatment group. There has been similar dialogue surrounding intensity of glucose control in critically ill inpatients³; here, the data suggest that hypoglycemic episodes may limit other benefits of aggressive treatment in the intensive care unit, such as reduced infection rates.

Not to be ignored is that the patients in all arms of the ACCORD trial fared far better than historical diabetic controls. The meticulous attention to management of blood pressure and LDL-C that all patients in the ACCORD trial received paid off. (If only we could do as well in our practices!) But what do we do about the sugar?

This large, well-done, ongoing trial deserves a detailed analysis for those of us who need to translate the conclusions regarding glucose control to our patients. This month in the Journal, I have invited Byron Hoogwerf, a clinical diabetologist, former internal medicine program director, well-published clinical trialist, and ACCORD investigator, to provide this analysis.⁴ His discussion is more detailed than what we often print purposefully, and it is well worth reading. Some issues simply can’t be understood as a sound bite.

The sound bites about these trials in the news have confused physicians and patients alike. But, as we have all experienced during this election year, to understand complex problems requires an in-depth analysis instead of a sound bite.

I was troubled by the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,² in which more patients who were treated with an intense hemoglobin A_1c-lowering strategy died (mostly of macrovascular events) than those treated with a standard strategy. Older data showing a beneficial effect of glucose-lowering on the microvascular complications of diabetes are solid. I did not understand the mechanistic basis of the ACCORD results, unless the very aggressive therapy caused many hypoglycemic events with catecholamine surges, resulting in stroke or myocardial infarction, or whether a problem with a specific drug arose more often in the intensive-treatment group. There has been similar dialogue surrounding intensity of glucose control in critically ill inpatients³; here, the data suggest that hypoglycemic episodes may limit other benefits of aggressive treatment in the intensive care unit, such as reduced infection rates.

Not to be ignored is that the patients in all arms of the ACCORD trial fared far better than historical diabetic controls. The meticulous attention to management of blood pressure and LDL-C that all patients in the ACCORD trial received paid off. (If only we could do as well in our practices!) But what do we do about the sugar?

This large, well-done, ongoing trial deserves a detailed analysis for those of us who need to translate the conclusions regarding glucose control to our patients. This month in the Journal, I have invited Byron Hoogwerf, a clinical diabetologist, former internal medicine program director, well-published clinical trialist, and ACCORD investigator, to provide this analysis.⁴ His discussion is more detailed than what we often print purposefully, and it is well worth reading. Some issues simply can’t be understood as a sound bite.

The sound bites about these trials in the news have confused physicians and patients alike. But, as we have all experienced during this election year, to understand complex problems requires an in-depth analysis instead of a sound bite.

I was troubled by the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,² in which more patients who were treated with an intense hemoglobin A_1c-lowering strategy died (mostly of macrovascular events) than those treated with a standard strategy. Older data showing a beneficial effect of glucose-lowering on the microvascular complications of diabetes are solid. I did not understand the mechanistic basis of the ACCORD results, unless the very aggressive therapy caused many hypoglycemic events with catecholamine surges, resulting in stroke or myocardial infarction, or whether a problem with a specific drug arose more often in the intensive-treatment group. There has been similar dialogue surrounding intensity of glucose control in critically ill inpatients³; here, the data suggest that hypoglycemic episodes may limit other benefits of aggressive treatment in the intensive care unit, such as reduced infection rates.

Not to be ignored is that the patients in all arms of the ACCORD trial fared far better than historical diabetic controls. The meticulous attention to management of blood pressure and LDL-C that all patients in the ACCORD trial received paid off. (If only we could do as well in our practices!) But what do we do about the sugar?

This large, well-done, ongoing trial deserves a detailed analysis for those of us who need to translate the conclusions regarding glucose control to our patients. This month in the Journal, I have invited Byron Hoogwerf, a clinical diabetologist, former internal medicine program director, well-published clinical trialist, and ACCORD investigator, to provide this analysis.⁴ His discussion is more detailed than what we often print purposefully, and it is well worth reading. Some issues simply can’t be understood as a sound bite.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial^1–5 was designed primarily to address, in patients with type 2 diabetes at high risk of cardiovascular events, whether intensive glucose control would result in a lower risk of atherosclerotic disease events or death than would standard treatment.

It was widely expected that intensive treatment would confer either modest benefit or, at worst, no benefit. However, the glucose-lowering arm of the trial was terminated early because of a higher mortality rate in the intensively treated group. (The ACCORD trial has two other arms, which concern blood pressure and lipid-lowering, and these are continuing.)

In earlier trials in type 2 diabetes, concerns had been raised about an increased risk of cardiovascular events and possibly death associated with glucose-lowering drugs, hypoglycemia itself, or both, and these were well known when ACCORD was convened. ACCORD was very carefully designed and included careful adjudication of each cardiovascular event and death, including whether hypoglycemia might have been a proximate cause of some sudden deaths.⁵

Therefore, the surprising result of the higher mortality rate with intensive glycemic control in ACCORD will be fodder for discussion in many arenas over the next several years, and it poses some challenges for physicians and patients in determining treatment goals, as well as for organizations that write clinical practice guidelines (and perhaps organizations involved in pay-for-performance based on these guidelines).

Still, I believe that the ACCORD results should not substantially change our approach to treatment goals in type 2 diabetes, although hemoglobin A_1c targets below 6% may not have much added value for cardiovascular risk reduction. The low overall mortality rate in all the arms of the ACCORD trial emphasizes the importance of lifestyle modification, lipid and blood pressure therapy, and encouragement of aspirin use in all patients with type 2 diabetes.

This article reflects my views as a practicing diabetologist and clinical trialist (I was an investigator in the ACCORD trial) with a long-standing interest in clinical trials and in how the results influence clinical practice. The views I express herein may not reflect the views of other ACCORD investigators, the National Heart, Lung, and Blood Institute (NHLBI), the ACCORD trial coordinating center at Wake Forest University, or its data safety and monitoring board.

RISK OF CORONARY DISEASE INCREASES WITH GLUCOSE

Many observational studies^6–10 have shown that the risk of cardiovascular disease, especially coronary heart disease, is two to five times higher in people with diabetes mellitus than in people without diabetes. The risk appears to be continuous, so the higher one’s glucose or hemoglobin A_1c, the higher the risk.⁶ This risk even extends to glucose values well below the threshold values currently used to diagnose diabetes mellitus.⁶ Since there is no glucose threshold for coronary heart disease, the term dysglycemia (rather than hyperglycemia) has been proposed to note the relationship between glucose and coronary heart disease. (The glucose threshold for microvascular complications of diabetes, such as retinopathy and nephropathy, appears to be between 110 and 126 mg/dL).

The clustering of multiple coronary risk factors such as obesity, dyslipidemia, and hypertension has always raised the question of whether glucose is a culprit in coronary risk or whether it simply “runs in bad company.”

EARLIER CLINICAL TRIALS SUGGEST INTENSIVE TREATMENT RAISES RISK

Even though it has been widely believed that intensive glucose-lowering would reduce cardiovascular risk in type 2 diabetes, there have been hints in previous studies that some intensive-treatment regimens might increase risk.

Two large randomized clinical trials and one small one (discussed below) addressed whether glucose control would reduce the risk of atherosclerotic vascular disease events. In each of them, an increased risk of cardiovascular events and possibly of death was seen in at least one intensively treated group.

In the following discussion, I have calculated all of the death rates as the number of deaths per 1,000 patients per year, based on published study results. In this way, we can compare the rates in the various studies (including ACCORD), regardless of the trial duration.

The university group Diabetes Program: Controvery about tolbutamide therapy

The University Group Diabetes Program (UGDP)^11–16 included about 1,000 participants randomized to five treatments: tolbutamide (Orinase, a sulfonylurea), insulin in a fixed dose based on body weight, insulin in adjusted doses based on fasting glucose levels, placebo, and (later) phenformin.

In the 1970s, when the UGDP was carried out, randomized clinical trials were uncommon. Like other trials from that era, the UGDP was underpowered by today’s standards and did not have a data safety and monitoring board.

Rates of cardiovascular events and deaths (per 1,000 patient-years):

• 25 (tolbutamide group)
• 12 (placebo group).

The two insulin groups did not differ from the placebo group in their rates of cardiovascular events or death.¹⁵ The tolbutamide arm was stopped, and the ensuing controversy about how to interpret the trial results lasted for more than a decade. It also resulted in a black-box warning for tolbutamide and all subsequent sulfonylureas.

The United Kingdom Prospective Diabetes Study (UKPDS)^17–27 was launched in 1977. A cohort of 5,102 patients (mean age 54 years) with newly diagnosed type 2 diabetes mellitus followed a “prudent diet” for the first 3 to 4 months. Then, if their fasting glucose levels were in the range of 6.1 to 15 mmol/L (110–270 mg/dL), they were randomized to receive various treatments.

Patients who were not obese were randomized to receive either intensive treatment or conventional treatment. The intensive-treatment group received either insulin or a sulfonylurea (chlorpropamide [Diabinese], glibenclamide, or glipizide [Glucotrol]); the conventional-treatment group received diet therapy. The sulfonylurea arm was included partly to address the UGDP results.

Patients who were obese were randomized to receive one of three treatments: intensive treatment (with the agents listed above), conventional treatment, or metformin (Fortamet, Glucophage).

The mean in-trial hemoglobin A_1c level in the intensive-treatment group was 7.0%, compared with 7.9% in the conventional-treatment group.

After a mean follow-up of more than 10 years, the incidence of myocardial infarction was 16% lower in the intensive-treatment group, but the difference was not statistically significant (P = .052).

Rates of death from all causes among nonobese subjects (per 1,000 patient-years):

• 18.2–20.5 (intensive-treatment group)
• 19.9 (conventional-treatment group).

In the obese patients who received metformin, the incidence of myocardial infarction was lower than in the conventional-treatment group but not the intensive-treatment group.

Rates of death among obese patients (per 1,000 patient-years):

• 13.5 (metformin group)
• 18.9 (intensive-treatment group)
• 20.6 (conventional-treatment group).

However, a small subset (n = 587) of the original group assigned to sulfonylurea therapy whose glycemic control deteriorated during the trial were rerandomized to continue to receive a sulfonylurea alone or to have metformin added. There was a statistically significantly higher rate of cardiovascular events and a nonsignificantly higher rate of total mortality in the metformin-plus-sulfonylurea group (30.3 per 1,000 patient-years) than in the sulfonylurea-only group (19.1 per 1,000 patient-years).

These data suggested that the way glucose-lowering was achieved might be as important as the glucose levels actually achieved. However, no definite conclusions could be drawn.

In an editorial on the UKPDS, Nathan²⁶ made a comment that may have been prescient in terms of the ACCORD trial: “Professional organizations will now scramble to decide how to translate the UKPDS results … Whether the UKPDS firmly establishes the choice of any one therapy…or any combination of therapies for the long-term treatment of type 2 diabetes is more questionable.”²⁶

Veterans Administration feasibility study

A Veterans Administration feasibility study^28,29 included 153 men (mean age 60) with type 2 diabetes (mean duration 7.8 years) who received either conventional therapy (a single daily dose of insulin) or intensive therapy (multiple doses of insulin plus a sulfonylurea). Over a mean of 27 months, the intensive-therapy group achieved a hemoglobin A_1c level that was 2 percentage points lower than in the conventional-therapy group.

At 2.25 years of follow-up, cardiovascular events had occurred in 24 (24%) of the intensive-therapy group and in 16 (20%) of the standard-therapy group (P = .10).

Rates of death from all causes (per 1,000 patient-years):

• 28.9 (intensive-treatment group)
• 17.5 (conventional-treatment group).

ACCORD TRIAL DESIGN

The primary outcome measured was the combined incidence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Secondary outcomes included death from any cause. The study is also evaluating the effect of intensive treatment on microvascular disease, hypoglycemia, cognition, quality of life, and cost-effectiveness.

The ACCORD study was designed to have 89% power to detect a 15% treatment effect of intensive glycemic control compared with standard glycemic control for the primary end point.

ACCORD RESULTS

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

Rates of death from any cause (per 1,000 patient-years):

• 14 (intensive-treatment group)
• 11 (standard-treatment group).

In the analyses available at the time that this study arm closed, the excess mortality was not attributable to any particular treatment regimen. In particular, rosiglitazone (Avandia) use did not contribute to the excess mortality. (Of note, 91.2% of the intensive-treatment group and 57.5% of the conventional-treatment group had been treated with rosiglitazone, with more than 19,000 patient-years of rosiglitazone exposure). The excess mortality was also not attributable to hypoglycemia immediately proximate to the death.

The ACCORD trial’s data safety and monitoring board recommended that this arm of the study be discontinued for safety reasons, and this recommendation was accepted by the NHLBI project office. All participants were notified by letter before the trial results were announced publicly, and all intensive-therapy group participants are now being treated by the protocol used in the standard-therapy group.¹

FEWER DEATHS IN ACCORD THAN IN OTHER STUDIES IN DIABETES

The mortality rates in both arms of ACCORD were much lower than in other observational studies and clinical trials in type 2 diabetes.

The National Health and Nutrition Education Survey (NHANES),³⁰ conducted from 1971 to 1975, included 14,374 people with diabetes between the ages of 25 and 74. Many of them were younger than the ACCORD patients, but two NHANES age-groups overlapped the ACCORD cohort. Rates of death from any cause at 22 years (per 1,000 patient-years):

• 39.7 (ages 45–64)
• 89.7 (ages 65–74).

The NHANES cohort would not have been treated as vigorously for coronary risk and other common causes of death.

UGDP, UKPDS. Death rates in the glucose-lowering trials of type 2 diabetes mellitus cited above were typically in the range of 20 deaths per 1,000 patient-years but were as high as 30 deaths per 1,000 patient-years in the UGDP tolbutamide group¹⁶ and the UK-PDS sulfonylurea-plus-metformin group.^20,22,26

Steno-2.³¹ Half of 160 patients with type 2 diabetes were randomized to intensive strategies for controlling glucose, lipids, and blood pressure and for taking aspirin and angiotensin-converting enzyme inhibitors and following a healthy lifestyle. The other half received conventional therapy. Even in the intensive-treatment group, the mortality rate at 13 years was higher than in ACCORD. Rates of death from any cause (per 1,000 patient years):

• 22.5 (intensive-treatment group)
• 37.6 (conventional-treatment group).

After the ACCORD results were presented, two other trials addressing the question of whether lower hemoglobin A_1c would reduce cardiovascular risk in type 2 diabetes have reported their outcomes:

The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),^32,33 with 11,140 patients, had a target hemoglobin A_1c of 6.5% in an intensive-treatment group and 7.3% in a usual-treatment group. The intensive-treatment group showed no difference in the rates of major macrovascular events (HR 0.94, 95% CI 0.84–1.06, P = .32) or all-cause mortality (HR 0.93, 95% CI 0.83–1.06, P = .32). The overall death rate in ADVANCE (about 18 deaths per 1,000 patient-years) was higher than in ACCORD.

The Veterans Administration Diabetes Trial included 1,791 patients.³⁴ Like the ADVANCE trial, it also found no difference in major cardiovascular outcomes (HR 0.868, P = .11) or cardiovascular mortality rates (HR 1.258, P = .36) with intensive therapy vs conventional therapy, ie, achieved hemoglobin A_1c levels of 6.9% vs 8.4% (presented at the American Diabetes Association 2008 Scientific Sessions). Hypoglycemia was associated with an increased risk of death in the standard-treatment group.

An analysis suggested that patients with a shorter duration of diabetes may have had cardiovascular benefit from intensive glucose-lowering, while those who had had it longer may have had increased risk associated with the more intensive therapy. The rate of death from all causes appears to have been higher than in ACCORD, but this could not be determined accurately from the presentations.

Comment. Thus, the ACCORD cohort as a whole has had strikingly lower death rates than in these other studies. The fact that all participants had lower glucose levels on therapy than at baseline may possibly contribute to these lower death rates. In addition, all ACCORD participants in the lipid arm received a statin; all participants in the blood pressure arm had their blood pressure lowered to levels below those commonly seen in clinical practice; participants were encouraged to exercise regularly; most participants were given diet instruction; and other healthy behaviors such as aspirin use, regular follow-up with primary care physicians, and recommendations about smoking were encouraged throughout the study. These comprehensive strategies may represent better care and thus result in lower death rates than in other studies.

POSSIBLE EXPLANATIONS FOR THE ACCORD OUTCOMES

The ACCORD trial has already stimulated fierce debate about the reasons for the higher mortality rate in the intensive-treatment group. With longer follow-up, some new risk factors for death may be identified that are not evident in the analyses of the current 460 deaths. What follows are some of my thoughts, with the caveat that they are not confirmed (supported statistically) by any currently available analyses from ACCORD.

It seems unlikely that lower glucose values as reflected by lower hemoglobin A_1c values in the intensive-treatment group are an a priori explanation for the observed differences in mortality rates—especially since the mortality rates were lower than in the NHANES and clinical trial data sets cited above. If we assume that a type 1 statistical error (finding a difference where no difference actually exists) does not explain the findings, then at least four reasonable postulates exist:

Hypoglycemia may have some adverse effect, either acutely or from recurrent events that trigger a catecholamine response with associated risk for arrhythmia or increased coronary heart disease risk. However, the investigators analyzed each death to determine whether hypoglycemia was a contributing cause, and they found no statistically significant relationship between hypoglycemia and death in the intensive-treatment group.

Weight gain is common with intensive therapy. Obesity may be associated with greater cytokine production, higher concentrations of clotting factors, higher levels of free fatty acids, and other potential contributors to the risk of coronary heart disease and death. Currently, the ACCORD analyses do not suggest that weight gain explains the higher death rate.

Medications such as rosiglitazone, sulfonylureas, and the combination of a sulfonylurea plus metformin have been previously associated with increased death rates in some observational and intervention trials. These studies had some serious methodologic limitations (eg, absence of risk adjustment, events not adjudicated, small study cohorts, wide variation in study cohort characteristics) and small numbers of events.^{11–13,16,26,35} ACCORD analyses have not shown that any single glucose-lowering agent—including rosiglitazone—or combination of agents explains the death rates.

The stress of maintaining glycemic control has been speculated to have in some way contributed to an increased risk. To achieve intensive control, patients had to have frequent contact with their health care providers, they were often told that their hemoglobin A_1c values were “too high” even when they were well below those in the American Diabetes Association guidelines, and they had to follow complex glucose-lowering regimens.

Semiquantitative measures of overall attitudes about health exist (eg, the “Feeling Thermometer” scale), but stress was not measured quantitatively in the ACCORD trial.

IMPLICATIONS OF ACCORD

In practice, most clinicians believe that the target glucose level in patients with type 2 diabetes should be as low as safely possible. This approach does not need to be modified on the basis of current information from ACCORD.

To be safe, regimens should be associated with a low risk of hypoglycemia and a low risk of weight gain. Use of combinations of medications that work by different mechanisms is still prudent. Agents should be used that may have favorable effects on other cardiovascular risk factors (eg, lipids, blood pressure, visceral fat).

Hemoglobin A_1c targets below 7% are not precluded in all patients on the basis of the ACCORD results, though values lower than 6% may not have much added benefit for cardiovascular risk reduction. We should note that hemoglobin A_1c was reduced in all ACCORD participants and that death rates were lower than in many other type 2 diabetic cohorts. Pending data on other outcomes in ACCORD (nephropathy, retinopathy, dementia, fracture risk), I believe it is premature for organizations to change their proposed hemoglobin A_1c targets,^36,37 as none have proposed values as low as the target in the ACCORD intensive-treatment group. At present, no class of glucose-lowering agents needs to be excluded from consideration on the basis of the ACCORD data.

The overall low rates of death in this population at high risk of coronary heart disease deserve comment. Not only are they lower than in other glucose-lowering trials, but they are also lower than in a number of studies of mortality in diabetes cohorts. As noted above, multiple risk factors for coronary heart disease and death were (and are) addressed in the ACCORD study participants, including repeated recommendation for lifestyle modification, intervention arms with lipid and blood pressure therapy, encouragement of aspirin use, and regular follow-up with health care providers for risk factors not managed by the ACCORD trial protocol. It is likely that multiple approaches to reducing the risk of cardiovascular disease contributed to this low mortality rate and that similar approaches will reduce the risk of coronary disease and death in regular clinical practice.

The ACCORD lipid and blood pressure arms are continuing, with results expected in 2010. The future results from ACCORD as well as from several glucose-lowering trials currently in progress (ADVANCE,^32,33 Veteran’s Administration,³⁴ Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI-2D]³⁸) will likely help refine our understanding of the effects of glucose-lowering, glucose-lowering strategies and targets, and multiple interventions on coronary events and all-cause mortality.

For now, any strategy that lowers glucose and is associated with a low risk of hypoglycemia and does not cause excessive weight gain should be considered appropriate in patients with type 2 diabetes.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial^1–5 was designed primarily to address, in patients with type 2 diabetes at high risk of cardiovascular events, whether intensive glucose control would result in a lower risk of atherosclerotic disease events or death than would standard treatment.

It was widely expected that intensive treatment would confer either modest benefit or, at worst, no benefit. However, the glucose-lowering arm of the trial was terminated early because of a higher mortality rate in the intensively treated group. (The ACCORD trial has two other arms, which concern blood pressure and lipid-lowering, and these are continuing.)

In earlier trials in type 2 diabetes, concerns had been raised about an increased risk of cardiovascular events and possibly death associated with glucose-lowering drugs, hypoglycemia itself, or both, and these were well known when ACCORD was convened. ACCORD was very carefully designed and included careful adjudication of each cardiovascular event and death, including whether hypoglycemia might have been a proximate cause of some sudden deaths.⁵

Therefore, the surprising result of the higher mortality rate with intensive glycemic control in ACCORD will be fodder for discussion in many arenas over the next several years, and it poses some challenges for physicians and patients in determining treatment goals, as well as for organizations that write clinical practice guidelines (and perhaps organizations involved in pay-for-performance based on these guidelines).

Still, I believe that the ACCORD results should not substantially change our approach to treatment goals in type 2 diabetes, although hemoglobin A_1c targets below 6% may not have much added value for cardiovascular risk reduction. The low overall mortality rate in all the arms of the ACCORD trial emphasizes the importance of lifestyle modification, lipid and blood pressure therapy, and encouragement of aspirin use in all patients with type 2 diabetes.

This article reflects my views as a practicing diabetologist and clinical trialist (I was an investigator in the ACCORD trial) with a long-standing interest in clinical trials and in how the results influence clinical practice. The views I express herein may not reflect the views of other ACCORD investigators, the National Heart, Lung, and Blood Institute (NHLBI), the ACCORD trial coordinating center at Wake Forest University, or its data safety and monitoring board.

RISK OF CORONARY DISEASE INCREASES WITH GLUCOSE

Many observational studies^6–10 have shown that the risk of cardiovascular disease, especially coronary heart disease, is two to five times higher in people with diabetes mellitus than in people without diabetes. The risk appears to be continuous, so the higher one’s glucose or hemoglobin A_1c, the higher the risk.⁶ This risk even extends to glucose values well below the threshold values currently used to diagnose diabetes mellitus.⁶ Since there is no glucose threshold for coronary heart disease, the term dysglycemia (rather than hyperglycemia) has been proposed to note the relationship between glucose and coronary heart disease. (The glucose threshold for microvascular complications of diabetes, such as retinopathy and nephropathy, appears to be between 110 and 126 mg/dL).

The clustering of multiple coronary risk factors such as obesity, dyslipidemia, and hypertension has always raised the question of whether glucose is a culprit in coronary risk or whether it simply “runs in bad company.”

EARLIER CLINICAL TRIALS SUGGEST INTENSIVE TREATMENT RAISES RISK

Even though it has been widely believed that intensive glucose-lowering would reduce cardiovascular risk in type 2 diabetes, there have been hints in previous studies that some intensive-treatment regimens might increase risk.

Two large randomized clinical trials and one small one (discussed below) addressed whether glucose control would reduce the risk of atherosclerotic vascular disease events. In each of them, an increased risk of cardiovascular events and possibly of death was seen in at least one intensively treated group.

In the following discussion, I have calculated all of the death rates as the number of deaths per 1,000 patients per year, based on published study results. In this way, we can compare the rates in the various studies (including ACCORD), regardless of the trial duration.

The university group Diabetes Program: Controvery about tolbutamide therapy

The University Group Diabetes Program (UGDP)^11–16 included about 1,000 participants randomized to five treatments: tolbutamide (Orinase, a sulfonylurea), insulin in a fixed dose based on body weight, insulin in adjusted doses based on fasting glucose levels, placebo, and (later) phenformin.

In the 1970s, when the UGDP was carried out, randomized clinical trials were uncommon. Like other trials from that era, the UGDP was underpowered by today’s standards and did not have a data safety and monitoring board.

Rates of cardiovascular events and deaths (per 1,000 patient-years):

• 25 (tolbutamide group)
• 12 (placebo group).

The two insulin groups did not differ from the placebo group in their rates of cardiovascular events or death.¹⁵ The tolbutamide arm was stopped, and the ensuing controversy about how to interpret the trial results lasted for more than a decade. It also resulted in a black-box warning for tolbutamide and all subsequent sulfonylureas.

The United Kingdom Prospective Diabetes Study (UKPDS)^17–27 was launched in 1977. A cohort of 5,102 patients (mean age 54 years) with newly diagnosed type 2 diabetes mellitus followed a “prudent diet” for the first 3 to 4 months. Then, if their fasting glucose levels were in the range of 6.1 to 15 mmol/L (110–270 mg/dL), they were randomized to receive various treatments.

Patients who were not obese were randomized to receive either intensive treatment or conventional treatment. The intensive-treatment group received either insulin or a sulfonylurea (chlorpropamide [Diabinese], glibenclamide, or glipizide [Glucotrol]); the conventional-treatment group received diet therapy. The sulfonylurea arm was included partly to address the UGDP results.

Patients who were obese were randomized to receive one of three treatments: intensive treatment (with the agents listed above), conventional treatment, or metformin (Fortamet, Glucophage).

The mean in-trial hemoglobin A_1c level in the intensive-treatment group was 7.0%, compared with 7.9% in the conventional-treatment group.

After a mean follow-up of more than 10 years, the incidence of myocardial infarction was 16% lower in the intensive-treatment group, but the difference was not statistically significant (P = .052).

Rates of death from all causes among nonobese subjects (per 1,000 patient-years):

• 18.2–20.5 (intensive-treatment group)
• 19.9 (conventional-treatment group).

In the obese patients who received metformin, the incidence of myocardial infarction was lower than in the conventional-treatment group but not the intensive-treatment group.

Rates of death among obese patients (per 1,000 patient-years):

• 13.5 (metformin group)
• 18.9 (intensive-treatment group)
• 20.6 (conventional-treatment group).

However, a small subset (n = 587) of the original group assigned to sulfonylurea therapy whose glycemic control deteriorated during the trial were rerandomized to continue to receive a sulfonylurea alone or to have metformin added. There was a statistically significantly higher rate of cardiovascular events and a nonsignificantly higher rate of total mortality in the metformin-plus-sulfonylurea group (30.3 per 1,000 patient-years) than in the sulfonylurea-only group (19.1 per 1,000 patient-years).

These data suggested that the way glucose-lowering was achieved might be as important as the glucose levels actually achieved. However, no definite conclusions could be drawn.

In an editorial on the UKPDS, Nathan²⁶ made a comment that may have been prescient in terms of the ACCORD trial: “Professional organizations will now scramble to decide how to translate the UKPDS results … Whether the UKPDS firmly establishes the choice of any one therapy…or any combination of therapies for the long-term treatment of type 2 diabetes is more questionable.”²⁶

Veterans Administration feasibility study

A Veterans Administration feasibility study^28,29 included 153 men (mean age 60) with type 2 diabetes (mean duration 7.8 years) who received either conventional therapy (a single daily dose of insulin) or intensive therapy (multiple doses of insulin plus a sulfonylurea). Over a mean of 27 months, the intensive-therapy group achieved a hemoglobin A_1c level that was 2 percentage points lower than in the conventional-therapy group.

At 2.25 years of follow-up, cardiovascular events had occurred in 24 (24%) of the intensive-therapy group and in 16 (20%) of the standard-therapy group (P = .10).

Rates of death from all causes (per 1,000 patient-years):

• 28.9 (intensive-treatment group)
• 17.5 (conventional-treatment group).

ACCORD TRIAL DESIGN

The primary outcome measured was the combined incidence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Secondary outcomes included death from any cause. The study is also evaluating the effect of intensive treatment on microvascular disease, hypoglycemia, cognition, quality of life, and cost-effectiveness.

The ACCORD study was designed to have 89% power to detect a 15% treatment effect of intensive glycemic control compared with standard glycemic control for the primary end point.

ACCORD RESULTS

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

Rates of death from any cause (per 1,000 patient-years):

• 14 (intensive-treatment group)
• 11 (standard-treatment group).

In the analyses available at the time that this study arm closed, the excess mortality was not attributable to any particular treatment regimen. In particular, rosiglitazone (Avandia) use did not contribute to the excess mortality. (Of note, 91.2% of the intensive-treatment group and 57.5% of the conventional-treatment group had been treated with rosiglitazone, with more than 19,000 patient-years of rosiglitazone exposure). The excess mortality was also not attributable to hypoglycemia immediately proximate to the death.

The ACCORD trial’s data safety and monitoring board recommended that this arm of the study be discontinued for safety reasons, and this recommendation was accepted by the NHLBI project office. All participants were notified by letter before the trial results were announced publicly, and all intensive-therapy group participants are now being treated by the protocol used in the standard-therapy group.¹

FEWER DEATHS IN ACCORD THAN IN OTHER STUDIES IN DIABETES

The mortality rates in both arms of ACCORD were much lower than in other observational studies and clinical trials in type 2 diabetes.

The National Health and Nutrition Education Survey (NHANES),³⁰ conducted from 1971 to 1975, included 14,374 people with diabetes between the ages of 25 and 74. Many of them were younger than the ACCORD patients, but two NHANES age-groups overlapped the ACCORD cohort. Rates of death from any cause at 22 years (per 1,000 patient-years):

• 39.7 (ages 45–64)
• 89.7 (ages 65–74).

The NHANES cohort would not have been treated as vigorously for coronary risk and other common causes of death.

UGDP, UKPDS. Death rates in the glucose-lowering trials of type 2 diabetes mellitus cited above were typically in the range of 20 deaths per 1,000 patient-years but were as high as 30 deaths per 1,000 patient-years in the UGDP tolbutamide group¹⁶ and the UK-PDS sulfonylurea-plus-metformin group.^20,22,26

Steno-2.³¹ Half of 160 patients with type 2 diabetes were randomized to intensive strategies for controlling glucose, lipids, and blood pressure and for taking aspirin and angiotensin-converting enzyme inhibitors and following a healthy lifestyle. The other half received conventional therapy. Even in the intensive-treatment group, the mortality rate at 13 years was higher than in ACCORD. Rates of death from any cause (per 1,000 patient years):

• 22.5 (intensive-treatment group)
• 37.6 (conventional-treatment group).

After the ACCORD results were presented, two other trials addressing the question of whether lower hemoglobin A_1c would reduce cardiovascular risk in type 2 diabetes have reported their outcomes:

The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),^32,33 with 11,140 patients, had a target hemoglobin A_1c of 6.5% in an intensive-treatment group and 7.3% in a usual-treatment group. The intensive-treatment group showed no difference in the rates of major macrovascular events (HR 0.94, 95% CI 0.84–1.06, P = .32) or all-cause mortality (HR 0.93, 95% CI 0.83–1.06, P = .32). The overall death rate in ADVANCE (about 18 deaths per 1,000 patient-years) was higher than in ACCORD.

The Veterans Administration Diabetes Trial included 1,791 patients.³⁴ Like the ADVANCE trial, it also found no difference in major cardiovascular outcomes (HR 0.868, P = .11) or cardiovascular mortality rates (HR 1.258, P = .36) with intensive therapy vs conventional therapy, ie, achieved hemoglobin A_1c levels of 6.9% vs 8.4% (presented at the American Diabetes Association 2008 Scientific Sessions). Hypoglycemia was associated with an increased risk of death in the standard-treatment group.

An analysis suggested that patients with a shorter duration of diabetes may have had cardiovascular benefit from intensive glucose-lowering, while those who had had it longer may have had increased risk associated with the more intensive therapy. The rate of death from all causes appears to have been higher than in ACCORD, but this could not be determined accurately from the presentations.

Comment. Thus, the ACCORD cohort as a whole has had strikingly lower death rates than in these other studies. The fact that all participants had lower glucose levels on therapy than at baseline may possibly contribute to these lower death rates. In addition, all ACCORD participants in the lipid arm received a statin; all participants in the blood pressure arm had their blood pressure lowered to levels below those commonly seen in clinical practice; participants were encouraged to exercise regularly; most participants were given diet instruction; and other healthy behaviors such as aspirin use, regular follow-up with primary care physicians, and recommendations about smoking were encouraged throughout the study. These comprehensive strategies may represent better care and thus result in lower death rates than in other studies.

POSSIBLE EXPLANATIONS FOR THE ACCORD OUTCOMES

The ACCORD trial has already stimulated fierce debate about the reasons for the higher mortality rate in the intensive-treatment group. With longer follow-up, some new risk factors for death may be identified that are not evident in the analyses of the current 460 deaths. What follows are some of my thoughts, with the caveat that they are not confirmed (supported statistically) by any currently available analyses from ACCORD.

It seems unlikely that lower glucose values as reflected by lower hemoglobin A_1c values in the intensive-treatment group are an a priori explanation for the observed differences in mortality rates—especially since the mortality rates were lower than in the NHANES and clinical trial data sets cited above. If we assume that a type 1 statistical error (finding a difference where no difference actually exists) does not explain the findings, then at least four reasonable postulates exist:

Hypoglycemia may have some adverse effect, either acutely or from recurrent events that trigger a catecholamine response with associated risk for arrhythmia or increased coronary heart disease risk. However, the investigators analyzed each death to determine whether hypoglycemia was a contributing cause, and they found no statistically significant relationship between hypoglycemia and death in the intensive-treatment group.

Weight gain is common with intensive therapy. Obesity may be associated with greater cytokine production, higher concentrations of clotting factors, higher levels of free fatty acids, and other potential contributors to the risk of coronary heart disease and death. Currently, the ACCORD analyses do not suggest that weight gain explains the higher death rate.

Medications such as rosiglitazone, sulfonylureas, and the combination of a sulfonylurea plus metformin have been previously associated with increased death rates in some observational and intervention trials. These studies had some serious methodologic limitations (eg, absence of risk adjustment, events not adjudicated, small study cohorts, wide variation in study cohort characteristics) and small numbers of events.^{11–13,16,26,35} ACCORD analyses have not shown that any single glucose-lowering agent—including rosiglitazone—or combination of agents explains the death rates.

The stress of maintaining glycemic control has been speculated to have in some way contributed to an increased risk. To achieve intensive control, patients had to have frequent contact with their health care providers, they were often told that their hemoglobin A_1c values were “too high” even when they were well below those in the American Diabetes Association guidelines, and they had to follow complex glucose-lowering regimens.

Semiquantitative measures of overall attitudes about health exist (eg, the “Feeling Thermometer” scale), but stress was not measured quantitatively in the ACCORD trial.

IMPLICATIONS OF ACCORD

In practice, most clinicians believe that the target glucose level in patients with type 2 diabetes should be as low as safely possible. This approach does not need to be modified on the basis of current information from ACCORD.

To be safe, regimens should be associated with a low risk of hypoglycemia and a low risk of weight gain. Use of combinations of medications that work by different mechanisms is still prudent. Agents should be used that may have favorable effects on other cardiovascular risk factors (eg, lipids, blood pressure, visceral fat).

Hemoglobin A_1c targets below 7% are not precluded in all patients on the basis of the ACCORD results, though values lower than 6% may not have much added benefit for cardiovascular risk reduction. We should note that hemoglobin A_1c was reduced in all ACCORD participants and that death rates were lower than in many other type 2 diabetic cohorts. Pending data on other outcomes in ACCORD (nephropathy, retinopathy, dementia, fracture risk), I believe it is premature for organizations to change their proposed hemoglobin A_1c targets,^36,37 as none have proposed values as low as the target in the ACCORD intensive-treatment group. At present, no class of glucose-lowering agents needs to be excluded from consideration on the basis of the ACCORD data.

The overall low rates of death in this population at high risk of coronary heart disease deserve comment. Not only are they lower than in other glucose-lowering trials, but they are also lower than in a number of studies of mortality in diabetes cohorts. As noted above, multiple risk factors for coronary heart disease and death were (and are) addressed in the ACCORD study participants, including repeated recommendation for lifestyle modification, intervention arms with lipid and blood pressure therapy, encouragement of aspirin use, and regular follow-up with health care providers for risk factors not managed by the ACCORD trial protocol. It is likely that multiple approaches to reducing the risk of cardiovascular disease contributed to this low mortality rate and that similar approaches will reduce the risk of coronary disease and death in regular clinical practice.

The ACCORD lipid and blood pressure arms are continuing, with results expected in 2010. The future results from ACCORD as well as from several glucose-lowering trials currently in progress (ADVANCE,^32,33 Veteran’s Administration,³⁴ Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI-2D]³⁸) will likely help refine our understanding of the effects of glucose-lowering, glucose-lowering strategies and targets, and multiple interventions on coronary events and all-cause mortality.

For now, any strategy that lowers glucose and is associated with a low risk of hypoglycemia and does not cause excessive weight gain should be considered appropriate in patients with type 2 diabetes.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial^1–5 was designed primarily to address, in patients with type 2 diabetes at high risk of cardiovascular events, whether intensive glucose control would result in a lower risk of atherosclerotic disease events or death than would standard treatment.

It was widely expected that intensive treatment would confer either modest benefit or, at worst, no benefit. However, the glucose-lowering arm of the trial was terminated early because of a higher mortality rate in the intensively treated group. (The ACCORD trial has two other arms, which concern blood pressure and lipid-lowering, and these are continuing.)

In earlier trials in type 2 diabetes, concerns had been raised about an increased risk of cardiovascular events and possibly death associated with glucose-lowering drugs, hypoglycemia itself, or both, and these were well known when ACCORD was convened. ACCORD was very carefully designed and included careful adjudication of each cardiovascular event and death, including whether hypoglycemia might have been a proximate cause of some sudden deaths.⁵

Therefore, the surprising result of the higher mortality rate with intensive glycemic control in ACCORD will be fodder for discussion in many arenas over the next several years, and it poses some challenges for physicians and patients in determining treatment goals, as well as for organizations that write clinical practice guidelines (and perhaps organizations involved in pay-for-performance based on these guidelines).

Still, I believe that the ACCORD results should not substantially change our approach to treatment goals in type 2 diabetes, although hemoglobin A_1c targets below 6% may not have much added value for cardiovascular risk reduction. The low overall mortality rate in all the arms of the ACCORD trial emphasizes the importance of lifestyle modification, lipid and blood pressure therapy, and encouragement of aspirin use in all patients with type 2 diabetes.

This article reflects my views as a practicing diabetologist and clinical trialist (I was an investigator in the ACCORD trial) with a long-standing interest in clinical trials and in how the results influence clinical practice. The views I express herein may not reflect the views of other ACCORD investigators, the National Heart, Lung, and Blood Institute (NHLBI), the ACCORD trial coordinating center at Wake Forest University, or its data safety and monitoring board.

RISK OF CORONARY DISEASE INCREASES WITH GLUCOSE

Many observational studies^6–10 have shown that the risk of cardiovascular disease, especially coronary heart disease, is two to five times higher in people with diabetes mellitus than in people without diabetes. The risk appears to be continuous, so the higher one’s glucose or hemoglobin A_1c, the higher the risk.⁶ This risk even extends to glucose values well below the threshold values currently used to diagnose diabetes mellitus.⁶ Since there is no glucose threshold for coronary heart disease, the term dysglycemia (rather than hyperglycemia) has been proposed to note the relationship between glucose and coronary heart disease. (The glucose threshold for microvascular complications of diabetes, such as retinopathy and nephropathy, appears to be between 110 and 126 mg/dL).

The clustering of multiple coronary risk factors such as obesity, dyslipidemia, and hypertension has always raised the question of whether glucose is a culprit in coronary risk or whether it simply “runs in bad company.”

EARLIER CLINICAL TRIALS SUGGEST INTENSIVE TREATMENT RAISES RISK

Even though it has been widely believed that intensive glucose-lowering would reduce cardiovascular risk in type 2 diabetes, there have been hints in previous studies that some intensive-treatment regimens might increase risk.

Two large randomized clinical trials and one small one (discussed below) addressed whether glucose control would reduce the risk of atherosclerotic vascular disease events. In each of them, an increased risk of cardiovascular events and possibly of death was seen in at least one intensively treated group.

In the following discussion, I have calculated all of the death rates as the number of deaths per 1,000 patients per year, based on published study results. In this way, we can compare the rates in the various studies (including ACCORD), regardless of the trial duration.

The university group Diabetes Program: Controvery about tolbutamide therapy

The University Group Diabetes Program (UGDP)^11–16 included about 1,000 participants randomized to five treatments: tolbutamide (Orinase, a sulfonylurea), insulin in a fixed dose based on body weight, insulin in adjusted doses based on fasting glucose levels, placebo, and (later) phenformin.

In the 1970s, when the UGDP was carried out, randomized clinical trials were uncommon. Like other trials from that era, the UGDP was underpowered by today’s standards and did not have a data safety and monitoring board.

Rates of cardiovascular events and deaths (per 1,000 patient-years):

• 25 (tolbutamide group)
• 12 (placebo group).

The two insulin groups did not differ from the placebo group in their rates of cardiovascular events or death.¹⁵ The tolbutamide arm was stopped, and the ensuing controversy about how to interpret the trial results lasted for more than a decade. It also resulted in a black-box warning for tolbutamide and all subsequent sulfonylureas.

The United Kingdom Prospective Diabetes Study (UKPDS)^17–27 was launched in 1977. A cohort of 5,102 patients (mean age 54 years) with newly diagnosed type 2 diabetes mellitus followed a “prudent diet” for the first 3 to 4 months. Then, if their fasting glucose levels were in the range of 6.1 to 15 mmol/L (110–270 mg/dL), they were randomized to receive various treatments.

Patients who were not obese were randomized to receive either intensive treatment or conventional treatment. The intensive-treatment group received either insulin or a sulfonylurea (chlorpropamide [Diabinese], glibenclamide, or glipizide [Glucotrol]); the conventional-treatment group received diet therapy. The sulfonylurea arm was included partly to address the UGDP results.

Patients who were obese were randomized to receive one of three treatments: intensive treatment (with the agents listed above), conventional treatment, or metformin (Fortamet, Glucophage).

The mean in-trial hemoglobin A_1c level in the intensive-treatment group was 7.0%, compared with 7.9% in the conventional-treatment group.

After a mean follow-up of more than 10 years, the incidence of myocardial infarction was 16% lower in the intensive-treatment group, but the difference was not statistically significant (P = .052).

Rates of death from all causes among nonobese subjects (per 1,000 patient-years):

• 18.2–20.5 (intensive-treatment group)
• 19.9 (conventional-treatment group).

In the obese patients who received metformin, the incidence of myocardial infarction was lower than in the conventional-treatment group but not the intensive-treatment group.

Rates of death among obese patients (per 1,000 patient-years):

• 13.5 (metformin group)
• 18.9 (intensive-treatment group)
• 20.6 (conventional-treatment group).

However, a small subset (n = 587) of the original group assigned to sulfonylurea therapy whose glycemic control deteriorated during the trial were rerandomized to continue to receive a sulfonylurea alone or to have metformin added. There was a statistically significantly higher rate of cardiovascular events and a nonsignificantly higher rate of total mortality in the metformin-plus-sulfonylurea group (30.3 per 1,000 patient-years) than in the sulfonylurea-only group (19.1 per 1,000 patient-years).

These data suggested that the way glucose-lowering was achieved might be as important as the glucose levels actually achieved. However, no definite conclusions could be drawn.

In an editorial on the UKPDS, Nathan²⁶ made a comment that may have been prescient in terms of the ACCORD trial: “Professional organizations will now scramble to decide how to translate the UKPDS results … Whether the UKPDS firmly establishes the choice of any one therapy…or any combination of therapies for the long-term treatment of type 2 diabetes is more questionable.”²⁶

Veterans Administration feasibility study

A Veterans Administration feasibility study^28,29 included 153 men (mean age 60) with type 2 diabetes (mean duration 7.8 years) who received either conventional therapy (a single daily dose of insulin) or intensive therapy (multiple doses of insulin plus a sulfonylurea). Over a mean of 27 months, the intensive-therapy group achieved a hemoglobin A_1c level that was 2 percentage points lower than in the conventional-therapy group.

At 2.25 years of follow-up, cardiovascular events had occurred in 24 (24%) of the intensive-therapy group and in 16 (20%) of the standard-therapy group (P = .10).

Rates of death from all causes (per 1,000 patient-years):

• 28.9 (intensive-treatment group)
• 17.5 (conventional-treatment group).

ACCORD TRIAL DESIGN

The primary outcome measured was the combined incidence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Secondary outcomes included death from any cause. The study is also evaluating the effect of intensive treatment on microvascular disease, hypoglycemia, cognition, quality of life, and cost-effectiveness.

The ACCORD study was designed to have 89% power to detect a 15% treatment effect of intensive glycemic control compared with standard glycemic control for the primary end point.

ACCORD RESULTS

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.

Rates of death from any cause (per 1,000 patient-years):

• 14 (intensive-treatment group)
• 11 (standard-treatment group).

In the analyses available at the time that this study arm closed, the excess mortality was not attributable to any particular treatment regimen. In particular, rosiglitazone (Avandia) use did not contribute to the excess mortality. (Of note, 91.2% of the intensive-treatment group and 57.5% of the conventional-treatment group had been treated with rosiglitazone, with more than 19,000 patient-years of rosiglitazone exposure). The excess mortality was also not attributable to hypoglycemia immediately proximate to the death.

The ACCORD trial’s data safety and monitoring board recommended that this arm of the study be discontinued for safety reasons, and this recommendation was accepted by the NHLBI project office. All participants were notified by letter before the trial results were announced publicly, and all intensive-therapy group participants are now being treated by the protocol used in the standard-therapy group.¹

FEWER DEATHS IN ACCORD THAN IN OTHER STUDIES IN DIABETES

The mortality rates in both arms of ACCORD were much lower than in other observational studies and clinical trials in type 2 diabetes.

The National Health and Nutrition Education Survey (NHANES),³⁰ conducted from 1971 to 1975, included 14,374 people with diabetes between the ages of 25 and 74. Many of them were younger than the ACCORD patients, but two NHANES age-groups overlapped the ACCORD cohort. Rates of death from any cause at 22 years (per 1,000 patient-years):

• 39.7 (ages 45–64)
• 89.7 (ages 65–74).

The NHANES cohort would not have been treated as vigorously for coronary risk and other common causes of death.

UGDP, UKPDS. Death rates in the glucose-lowering trials of type 2 diabetes mellitus cited above were typically in the range of 20 deaths per 1,000 patient-years but were as high as 30 deaths per 1,000 patient-years in the UGDP tolbutamide group¹⁶ and the UK-PDS sulfonylurea-plus-metformin group.^20,22,26

Steno-2.³¹ Half of 160 patients with type 2 diabetes were randomized to intensive strategies for controlling glucose, lipids, and blood pressure and for taking aspirin and angiotensin-converting enzyme inhibitors and following a healthy lifestyle. The other half received conventional therapy. Even in the intensive-treatment group, the mortality rate at 13 years was higher than in ACCORD. Rates of death from any cause (per 1,000 patient years):

• 22.5 (intensive-treatment group)
• 37.6 (conventional-treatment group).

After the ACCORD results were presented, two other trials addressing the question of whether lower hemoglobin A_1c would reduce cardiovascular risk in type 2 diabetes have reported their outcomes:

The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),^32,33 with 11,140 patients, had a target hemoglobin A_1c of 6.5% in an intensive-treatment group and 7.3% in a usual-treatment group. The intensive-treatment group showed no difference in the rates of major macrovascular events (HR 0.94, 95% CI 0.84–1.06, P = .32) or all-cause mortality (HR 0.93, 95% CI 0.83–1.06, P = .32). The overall death rate in ADVANCE (about 18 deaths per 1,000 patient-years) was higher than in ACCORD.

The Veterans Administration Diabetes Trial included 1,791 patients.³⁴ Like the ADVANCE trial, it also found no difference in major cardiovascular outcomes (HR 0.868, P = .11) or cardiovascular mortality rates (HR 1.258, P = .36) with intensive therapy vs conventional therapy, ie, achieved hemoglobin A_1c levels of 6.9% vs 8.4% (presented at the American Diabetes Association 2008 Scientific Sessions). Hypoglycemia was associated with an increased risk of death in the standard-treatment group.

An analysis suggested that patients with a shorter duration of diabetes may have had cardiovascular benefit from intensive glucose-lowering, while those who had had it longer may have had increased risk associated with the more intensive therapy. The rate of death from all causes appears to have been higher than in ACCORD, but this could not be determined accurately from the presentations.

Comment. Thus, the ACCORD cohort as a whole has had strikingly lower death rates than in these other studies. The fact that all participants had lower glucose levels on therapy than at baseline may possibly contribute to these lower death rates. In addition, all ACCORD participants in the lipid arm received a statin; all participants in the blood pressure arm had their blood pressure lowered to levels below those commonly seen in clinical practice; participants were encouraged to exercise regularly; most participants were given diet instruction; and other healthy behaviors such as aspirin use, regular follow-up with primary care physicians, and recommendations about smoking were encouraged throughout the study. These comprehensive strategies may represent better care and thus result in lower death rates than in other studies.

POSSIBLE EXPLANATIONS FOR THE ACCORD OUTCOMES

The ACCORD trial has already stimulated fierce debate about the reasons for the higher mortality rate in the intensive-treatment group. With longer follow-up, some new risk factors for death may be identified that are not evident in the analyses of the current 460 deaths. What follows are some of my thoughts, with the caveat that they are not confirmed (supported statistically) by any currently available analyses from ACCORD.

It seems unlikely that lower glucose values as reflected by lower hemoglobin A_1c values in the intensive-treatment group are an a priori explanation for the observed differences in mortality rates—especially since the mortality rates were lower than in the NHANES and clinical trial data sets cited above. If we assume that a type 1 statistical error (finding a difference where no difference actually exists) does not explain the findings, then at least four reasonable postulates exist:

Hypoglycemia may have some adverse effect, either acutely or from recurrent events that trigger a catecholamine response with associated risk for arrhythmia or increased coronary heart disease risk. However, the investigators analyzed each death to determine whether hypoglycemia was a contributing cause, and they found no statistically significant relationship between hypoglycemia and death in the intensive-treatment group.

Weight gain is common with intensive therapy. Obesity may be associated with greater cytokine production, higher concentrations of clotting factors, higher levels of free fatty acids, and other potential contributors to the risk of coronary heart disease and death. Currently, the ACCORD analyses do not suggest that weight gain explains the higher death rate.

Medications such as rosiglitazone, sulfonylureas, and the combination of a sulfonylurea plus metformin have been previously associated with increased death rates in some observational and intervention trials. These studies had some serious methodologic limitations (eg, absence of risk adjustment, events not adjudicated, small study cohorts, wide variation in study cohort characteristics) and small numbers of events.^{11–13,16,26,35} ACCORD analyses have not shown that any single glucose-lowering agent—including rosiglitazone—or combination of agents explains the death rates.

The stress of maintaining glycemic control has been speculated to have in some way contributed to an increased risk. To achieve intensive control, patients had to have frequent contact with their health care providers, they were often told that their hemoglobin A_1c values were “too high” even when they were well below those in the American Diabetes Association guidelines, and they had to follow complex glucose-lowering regimens.

Semiquantitative measures of overall attitudes about health exist (eg, the “Feeling Thermometer” scale), but stress was not measured quantitatively in the ACCORD trial.

IMPLICATIONS OF ACCORD

In practice, most clinicians believe that the target glucose level in patients with type 2 diabetes should be as low as safely possible. This approach does not need to be modified on the basis of current information from ACCORD.

To be safe, regimens should be associated with a low risk of hypoglycemia and a low risk of weight gain. Use of combinations of medications that work by different mechanisms is still prudent. Agents should be used that may have favorable effects on other cardiovascular risk factors (eg, lipids, blood pressure, visceral fat).

Hemoglobin A_1c targets below 7% are not precluded in all patients on the basis of the ACCORD results, though values lower than 6% may not have much added benefit for cardiovascular risk reduction. We should note that hemoglobin A_1c was reduced in all ACCORD participants and that death rates were lower than in many other type 2 diabetic cohorts. Pending data on other outcomes in ACCORD (nephropathy, retinopathy, dementia, fracture risk), I believe it is premature for organizations to change their proposed hemoglobin A_1c targets,^36,37 as none have proposed values as low as the target in the ACCORD intensive-treatment group. At present, no class of glucose-lowering agents needs to be excluded from consideration on the basis of the ACCORD data.

The overall low rates of death in this population at high risk of coronary heart disease deserve comment. Not only are they lower than in other glucose-lowering trials, but they are also lower than in a number of studies of mortality in diabetes cohorts. As noted above, multiple risk factors for coronary heart disease and death were (and are) addressed in the ACCORD study participants, including repeated recommendation for lifestyle modification, intervention arms with lipid and blood pressure therapy, encouragement of aspirin use, and regular follow-up with health care providers for risk factors not managed by the ACCORD trial protocol. It is likely that multiple approaches to reducing the risk of cardiovascular disease contributed to this low mortality rate and that similar approaches will reduce the risk of coronary disease and death in regular clinical practice.

The ACCORD lipid and blood pressure arms are continuing, with results expected in 2010. The future results from ACCORD as well as from several glucose-lowering trials currently in progress (ADVANCE,^32,33 Veteran’s Administration,³⁴ Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI-2D]³⁸) will likely help refine our understanding of the effects of glucose-lowering, glucose-lowering strategies and targets, and multiple interventions on coronary events and all-cause mortality.

For now, any strategy that lowers glucose and is associated with a low risk of hypoglycemia and does not cause excessive weight gain should be considered appropriate in patients with type 2 diabetes.

How many of your patients with type 2 diabetes or metabolic syndrome have a low-density lipoprotein cholesterol (LDL-C) level below the target of 100 mg/dL? Your answer, undoubtedly, is not enough of them. The good news we report in this article is that you can safely achieve the target more often, within 6 to 12 weeks, using a simple algorithm that helps you determine the optimal starting dose of a statin.

Good reason for concern. Individuals with coronary heart disease (CHD) or CHD risk equivalents such as diabetes have the highest cardiovascular risk and, according to the National Cholesterol Education Program (NCEP) III and other guidelines, must aim for the lowest target levels of LDL-C.¹ As the number of cardiovascular risk factors increases in a population, the percentage of patients reaching targets decreases^2,3 —to as low as 37% among those at highest risk.² The international Analysis and Understanding of Diabetes and Dyslipidaemia: Improving Treatment (AUDIT) survey found that out of all patients with type 2 diabetes being treated, only 54% achieved target.⁴

Type 2 diabetes purportedly imparts a cardiovascular risk comparable to that of a prior cardiovascular event.^1,5-7 Moreover, the outcome of such events in patients with diabetes is worse than in patients without diabetes, with approximately 7 out of 10 patients dying from the event or its complications.^7-9

The metabolic syndrome (MetSyn) also increases risk of cardiovascular events and mortality, even in individuals without diabetes or CHD.^10-13 In 1 study, the risks of all-cause and cardiovascular mortality in patients with MetSyn were 1.38 to 1.44 and 2.26 to 2.78, respectively, compared with those who did not have MetSyn.¹²

The algorithm we describe in this article was developed from results of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) trials. These trials were designed to assess whether, according to the degree of reduction required in LDL-C, an optimal starting dose of atorvastatin could be identified so that patients would achieve LDL-C targets quickly, with no change in the dose or with just one titration step, and regardless of statin use at baseline.

The main results of ACTFAST 1 and 2 have been published elsewhere.^14,15 We report specifically on a prespecified analysis of pooled results in the subset of patients with diabetes or MetSyn.

Methods

Patient population

We extracted the study population from prespecified pooling of data from ACTFAST 1 and 2,^14,15 which were 12-week, multicenter, prospective, open-label trials that used the same protocol. A full description of inclusion and exclusion criteria for ACTFAST has been published elsewhere.^14,15

Briefly, subjects were either statin-free or statin-treated at baseline, had CHD or a CHD equivalent, had an LDL-C level between 100 and 220 mg/dL (2.6-5.7 mmol/L) and triglycerides =600 mg/dL (6.8 mmol/L), and were willing to follow a recommended diet.

We excluded patients if they had used other lipid-lowering therapy in the prior 2 months (except for statins in the statin-treated study arm) or if they were receiving >40 mg/d of any statin. Patients taking atorvastatin at screening were excluded because the study's goal was to assess the benefits of switching over to a flexible starting dose of atorvastatin. We defined diabetes and MetSyn according to the American Diabetes Association criteria¹⁶ and the NCEP 2001 criteria,¹ respectively.

Doses reflected LDL-C baseline-target gap and prior statin use

If patients were statin free at baseline, we assigned them to 6 weeks of treatment with atorvastatin, at 10, 20, 40, or 80 mg/d, according to their baseline LDL-C level ( FIGURE 1 ). For patients who had been taking a statin at screening, starting doses of atorvastatin for each LDL-C increment were doubled.

If patients did not reach LDL-C targets at the end of 6 weeks, we titrated their regimen to the next higher dose for an additional 6 weeks. Patients initially allocated to receive atorvastatin at 80 mg who did not reach LDL-C targets continued at that dose, and we added a more intense therapeutic lifestyle intervention (NCEP II step 2 diet).¹

We obtained blood samples at baseline screening, week 6, and week 12, to measure 12-hour fasting serum lipid profiles and to make routine safety assessments (hematology and chemistry). Patients received dietary counseling at all visits.

The ACTFAST protocol and amendments were approved by appropriately constituted central or local institutional review boards, and all patients gave written informed consent.

FIGURE 1
How treatment doses were determined

Statin-free patients received a specified dose of atorvastatin according to their baseline low-density lipoprotein cholesterol (LDL-C) level. Patients who had been treated with another statin at screening received atorvastatin at a dose double that given to statin-free patients with equivalent LDL-C levels, for a maximum dose of 80 mg.

Primary efficacy outcome: LDL-C levels of <100 mg/dL

The primary efficacy outcome was the proportion of patients with either diabetes or MetSyn achieving NCEP Adult Treatment Panel-III target LDL-C levels of <100 mg/dL (<2.6 mmol/L) after 12 weeks of treatment.¹ Secondary efficacy parameters were described in ACTFAST 1.¹⁴

We analyzed data according to intention-to-treat (ITT), using the last observation carried forward (LOCF) for missing data. The ITT population consisted of all patients who took at least 1 dose of study medication, and had at least 1 subsequent assessment.

Results

Between January 2003 and February 2004, 3634 subjects were screened for ACTFAST 1 and 2, and 2717 patients were enrolled from 12 countries (Canada, Greece, Hungary, Ireland, Italy, Poland, Portugal, Russia, Slovakia, Spain, Switzerland, and the United Kingdom). Ethnicity was recorded for about 80% of patients; more than 90% were Caucasian.

Diabetes

The ITT population included 1024 patients with diabetes, of whom 97% had type 2 diabetes and 73% were statin-free ( TABLE 1 ). Baseline laboratory parameters are available online, in TABLE W1 .

After 12 weeks of treatment, 81% (95% confidence interval [CI], 77.8%-83.5%) of statin-free and 60% (95% CI, 53.9%-65.4%) of statin-treated patients with diabetes achieved LDLC target of <100 mg/dL ( FIGURE 2 ). In contrast, among patients without diabetes (n=1693), 77% (95% CI, 73.9%-79.3%) of statin-free and 59% (95% CI, 55.4%-62.5%) of statin-treated patients achieved target.

For diabetes patients, mean percent reductions in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C and apolipoprotein B (apo B) were significant vs baseline for all doses in both statin-free and statin-treated subjects ( TABLE 2 ). Significant increases in HDL-C were seen only with the 10- and 80-mg doses in statin-free patients.

FIGURE 2
Patients who achieved an LDL-C level of <100 mg/dL
after receiving 12 weeks of atorvastatin

TABLE 1
Demographic profiles of patients with diabetes or metabolic syndrome
(This is an expanded version of the table that appeared in print.)

TABLE 2
Mean percent change (95% CI) in lipid levels from baseline when patients with diabetes or metabolic syndrome took atorvastatin
(This is an expanded version of the table that appeared in print.)

Metabolic syndrome

The ITT population included 1251 patients with MetSyn, of whom 56% also had diabetes and 67% were statin-free ( TABLE 1 ). Baseline laboratory parameters are in TABLE W1 .

After 12 weeks of treatment, 78% (95% CI, 74.9%-80.5%) of statin-free and 57% (95% CI, 52.5%-62.1%) of statin-treated patients achieved LDL-C target of <100 mg/dL ( FIGURE 2 ). Among patients without MetSyn (n=1454), 79% (95% CI, 76.2%-81.7%) of statin-free and 61% (95% CI, 56.8%-64.6%) of statin-treated patients achieved target. (Because of missing data, the presence or absence of MetSyn could not be confirmed in 12 patients.)

Mean percent reductions for MetSyn patients in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C, and apo B were significant vs baseline for all doses in both statin-free and statin-treated patients ( TABLE 2 ). HDL-C increased significantly in the 10- and 20-mg statin-free groups and in the 40-mg statin-treated group.

Treatment was well tolerated

The incidences of treatment-related adverse events were similar in all patient groups, at around 10%. Most events were mild to moderate, with severe events reported in only 0.5% and 0.8% of patients with diabetes and MetSyn, respectively. Incidences of treatment-related musculoskeletal adverse events were 1.9% and 2%, respectively, in patients with and without diabetes; and were 1.7% and 2.3% in patients with and without MetSyn.

The incidence of elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times and creatine kinase (CK) >10 times the upper limit of normal were 1.1% and 0.1%, respectively, for patients with diabetes, and 0.9% and 0.08% for those with MetSyn, which did not differ from those of patients without diabetes (1.2% and 0%, respectively) or MetSyn (1.3% and 0%, respectively).

TABLE W1
Baseline lipid values for patients with diabetes or metabolic syndrome (mean ± SD)

Discussion

Despite their increased cardiovascular risk, patients with diabetes and MetSyn often do not reach lipid targets.¹⁷ In patients with diabetes, lowering LDL-C levels reduces the risk of a cardiovascular event by 25% to 50%.^18-23 Atorvastatin has demonstrated its efficacy for the primary prevention of cardiovascular events among patients with diabetes.^22,23

MetSyn also increases the risk of cardiovascular events and mortality.^10-13 Atorvastatin has been used effectively to achieve LDL-C goals in hypercholesterolemic patients with MetSyn.^24,25

Higher starting doses of statins are generally beneficial. This substudy of ACTFAST demonstrates that by initiating therapy at doses selected according to baseline LDL-C levels, 81% of statin-free and 60% of statin-treated subjects with diabetes and 78% of statin-free and 57% of statin-treated subjects with MetSyn achieved a target LDL-C of <100 mg/dL within 6 to 12 weeks. Among statin-treated patients, atorvastatin provided additional reduction in lipid parameters over what was achieved with the statin they had been using at baseline.

Other studies have also suggested that patients at high risk for cardiovascular events, such as those with diabetes or MetSyn, may benefit from starting therapy at a higher dose of atorvastatin.^14,15,26,27 In the New Atorvastatin Starting Doses: A Comparison (NASDAC) study, patients were randomized to receive various starting doses of atorvastatin, regardless of their baseline LDL-C value.²⁶ The proportion of patients with CHD or a CHD-equivalent (of whom 150 had diabetes) who achieved LDL-C target (<100 mg/dL) with 10, 20, 40, and 80 mg/d was 47%, 66%, 81% and 80%, respectively, demonstrating that a higher starting dose is required to achieve target.

However, lower doses may work depending on LDL-C levels. In contrast to NASDAC, statin-free patients with diabetes or MetSyn in ACTFAST showed better results on 10- and 20-mg doses, because baseline LDL-C was taken into account. The Atorvastatin Goal Achievement Across Risk Levels (ATGOAL) study used a design similar to ACTFAST, assigning patients with dyslipidemia to starting doses of atorvastatin for 8 weeks, at 10, 20, 40, or 80 mg, based on their CHD risk category and the magnitude of LDL-C reduction necessary to reach lipid targets.²⁷ Of the 1298 patients, 705 were at high CHD risk (43.8% with diabetes), and 81.1% of these high-risk patients achieved an LDL-C <100 mg/dL.

No safety issues arose when initiating atorvastatin at higher doses in patients with diabetes or MetSyn. The incidence of clinically elevated AST, ALT, or CK levels in ACTFAST was low and comparable to that reported in meta-analyses (0.96%).^28,29

Benefits of our dosing algorithm seem clear. Aggressive treatment with atorvastatin across the dose range improves LDL-C target achievement compared with usual care,^30,31 and current NCEP-III recommendations support the use of a higher initial dose in patients requiring large LDL-C reductions.¹ Atorva-statin is approved in many countries at starting doses ranging from 10 to 40 mg, with a titration to 80 mg, if needed, to achieve LDL-C target. ACTFAST suggests that, in patients with diabetes or MetSyn, initiation of atorvastatin at a dose appropriate for the required level of LDL-C reduction would facilitate achievement of LDL-C targets.

One meta-analysis of trials demonstrated that a 10-mg/dL reduction in LDL-C could result in a 5.4% reduction in major vascular events and a 3.1% reduction in all-cause mortality over 5 years.³² In our study, patients with diabetes or MetSyn experienced reductions in LDL-C of approximately 57 mg/dL, which, if maintained over 5 years, could be expected to translate into reductions of 30% in major vascular events and 17% in mortality. Therefore, a regimen that allows a larger number of high-risk patients to achieve substantial reductions in LDL-C levels quickly could significantly improve cardiovascular outcomes.

Limitations of our study include the fact that the trial was not blinded, the size of the dosing groups was unequal, and there was no control group. However, it is unlikely that reduction of LDL-C was due to chance. Also, this study was not designed to investigate the effect of lowering LDL-C on the incidence of cardiovascular events.

Correspondence
Lawrence A. Leiter, MD, University of Toronto, St. Michael's Hospital, 61 Queen St. E.,#6121Q, Toronto, Ontario, Canada. M5C 2T2; [email protected]

How many of your patients with type 2 diabetes or metabolic syndrome have a low-density lipoprotein cholesterol (LDL-C) level below the target of 100 mg/dL? Your answer, undoubtedly, is not enough of them. The good news we report in this article is that you can safely achieve the target more often, within 6 to 12 weeks, using a simple algorithm that helps you determine the optimal starting dose of a statin.

Good reason for concern. Individuals with coronary heart disease (CHD) or CHD risk equivalents such as diabetes have the highest cardiovascular risk and, according to the National Cholesterol Education Program (NCEP) III and other guidelines, must aim for the lowest target levels of LDL-C.¹ As the number of cardiovascular risk factors increases in a population, the percentage of patients reaching targets decreases^2,3 —to as low as 37% among those at highest risk.² The international Analysis and Understanding of Diabetes and Dyslipidaemia: Improving Treatment (AUDIT) survey found that out of all patients with type 2 diabetes being treated, only 54% achieved target.⁴

Type 2 diabetes purportedly imparts a cardiovascular risk comparable to that of a prior cardiovascular event.^1,5-7 Moreover, the outcome of such events in patients with diabetes is worse than in patients without diabetes, with approximately 7 out of 10 patients dying from the event or its complications.^7-9

The metabolic syndrome (MetSyn) also increases risk of cardiovascular events and mortality, even in individuals without diabetes or CHD.^10-13 In 1 study, the risks of all-cause and cardiovascular mortality in patients with MetSyn were 1.38 to 1.44 and 2.26 to 2.78, respectively, compared with those who did not have MetSyn.¹²

The algorithm we describe in this article was developed from results of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) trials. These trials were designed to assess whether, according to the degree of reduction required in LDL-C, an optimal starting dose of atorvastatin could be identified so that patients would achieve LDL-C targets quickly, with no change in the dose or with just one titration step, and regardless of statin use at baseline.

The main results of ACTFAST 1 and 2 have been published elsewhere.^14,15 We report specifically on a prespecified analysis of pooled results in the subset of patients with diabetes or MetSyn.

Methods

Patient population

We extracted the study population from prespecified pooling of data from ACTFAST 1 and 2,^14,15 which were 12-week, multicenter, prospective, open-label trials that used the same protocol. A full description of inclusion and exclusion criteria for ACTFAST has been published elsewhere.^14,15

Briefly, subjects were either statin-free or statin-treated at baseline, had CHD or a CHD equivalent, had an LDL-C level between 100 and 220 mg/dL (2.6-5.7 mmol/L) and triglycerides =600 mg/dL (6.8 mmol/L), and were willing to follow a recommended diet.

We excluded patients if they had used other lipid-lowering therapy in the prior 2 months (except for statins in the statin-treated study arm) or if they were receiving >40 mg/d of any statin. Patients taking atorvastatin at screening were excluded because the study's goal was to assess the benefits of switching over to a flexible starting dose of atorvastatin. We defined diabetes and MetSyn according to the American Diabetes Association criteria¹⁶ and the NCEP 2001 criteria,¹ respectively.

Doses reflected LDL-C baseline-target gap and prior statin use

If patients were statin free at baseline, we assigned them to 6 weeks of treatment with atorvastatin, at 10, 20, 40, or 80 mg/d, according to their baseline LDL-C level ( FIGURE 1 ). For patients who had been taking a statin at screening, starting doses of atorvastatin for each LDL-C increment were doubled.

If patients did not reach LDL-C targets at the end of 6 weeks, we titrated their regimen to the next higher dose for an additional 6 weeks. Patients initially allocated to receive atorvastatin at 80 mg who did not reach LDL-C targets continued at that dose, and we added a more intense therapeutic lifestyle intervention (NCEP II step 2 diet).¹

We obtained blood samples at baseline screening, week 6, and week 12, to measure 12-hour fasting serum lipid profiles and to make routine safety assessments (hematology and chemistry). Patients received dietary counseling at all visits.

The ACTFAST protocol and amendments were approved by appropriately constituted central or local institutional review boards, and all patients gave written informed consent.

FIGURE 1
How treatment doses were determined

Statin-free patients received a specified dose of atorvastatin according to their baseline low-density lipoprotein cholesterol (LDL-C) level. Patients who had been treated with another statin at screening received atorvastatin at a dose double that given to statin-free patients with equivalent LDL-C levels, for a maximum dose of 80 mg.

Primary efficacy outcome: LDL-C levels of <100 mg/dL

The primary efficacy outcome was the proportion of patients with either diabetes or MetSyn achieving NCEP Adult Treatment Panel-III target LDL-C levels of <100 mg/dL (<2.6 mmol/L) after 12 weeks of treatment.¹ Secondary efficacy parameters were described in ACTFAST 1.¹⁴

We analyzed data according to intention-to-treat (ITT), using the last observation carried forward (LOCF) for missing data. The ITT population consisted of all patients who took at least 1 dose of study medication, and had at least 1 subsequent assessment.

Results

Between January 2003 and February 2004, 3634 subjects were screened for ACTFAST 1 and 2, and 2717 patients were enrolled from 12 countries (Canada, Greece, Hungary, Ireland, Italy, Poland, Portugal, Russia, Slovakia, Spain, Switzerland, and the United Kingdom). Ethnicity was recorded for about 80% of patients; more than 90% were Caucasian.

Diabetes

The ITT population included 1024 patients with diabetes, of whom 97% had type 2 diabetes and 73% were statin-free ( TABLE 1 ). Baseline laboratory parameters are available online, in TABLE W1 .

After 12 weeks of treatment, 81% (95% confidence interval [CI], 77.8%-83.5%) of statin-free and 60% (95% CI, 53.9%-65.4%) of statin-treated patients with diabetes achieved LDLC target of <100 mg/dL ( FIGURE 2 ). In contrast, among patients without diabetes (n=1693), 77% (95% CI, 73.9%-79.3%) of statin-free and 59% (95% CI, 55.4%-62.5%) of statin-treated patients achieved target.

For diabetes patients, mean percent reductions in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C and apolipoprotein B (apo B) were significant vs baseline for all doses in both statin-free and statin-treated subjects ( TABLE 2 ). Significant increases in HDL-C were seen only with the 10- and 80-mg doses in statin-free patients.

FIGURE 2
Patients who achieved an LDL-C level of <100 mg/dL
after receiving 12 weeks of atorvastatin

TABLE 1
Demographic profiles of patients with diabetes or metabolic syndrome
(This is an expanded version of the table that appeared in print.)

TABLE 2
Mean percent change (95% CI) in lipid levels from baseline when patients with diabetes or metabolic syndrome took atorvastatin
(This is an expanded version of the table that appeared in print.)

Metabolic syndrome

The ITT population included 1251 patients with MetSyn, of whom 56% also had diabetes and 67% were statin-free ( TABLE 1 ). Baseline laboratory parameters are in TABLE W1 .

After 12 weeks of treatment, 78% (95% CI, 74.9%-80.5%) of statin-free and 57% (95% CI, 52.5%-62.1%) of statin-treated patients achieved LDL-C target of <100 mg/dL ( FIGURE 2 ). Among patients without MetSyn (n=1454), 79% (95% CI, 76.2%-81.7%) of statin-free and 61% (95% CI, 56.8%-64.6%) of statin-treated patients achieved target. (Because of missing data, the presence or absence of MetSyn could not be confirmed in 12 patients.)

Mean percent reductions for MetSyn patients in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C, and apo B were significant vs baseline for all doses in both statin-free and statin-treated patients ( TABLE 2 ). HDL-C increased significantly in the 10- and 20-mg statin-free groups and in the 40-mg statin-treated group.

Treatment was well tolerated

The incidences of treatment-related adverse events were similar in all patient groups, at around 10%. Most events were mild to moderate, with severe events reported in only 0.5% and 0.8% of patients with diabetes and MetSyn, respectively. Incidences of treatment-related musculoskeletal adverse events were 1.9% and 2%, respectively, in patients with and without diabetes; and were 1.7% and 2.3% in patients with and without MetSyn.

The incidence of elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times and creatine kinase (CK) >10 times the upper limit of normal were 1.1% and 0.1%, respectively, for patients with diabetes, and 0.9% and 0.08% for those with MetSyn, which did not differ from those of patients without diabetes (1.2% and 0%, respectively) or MetSyn (1.3% and 0%, respectively).

TABLE W1
Baseline lipid values for patients with diabetes or metabolic syndrome (mean ± SD)

Discussion

Despite their increased cardiovascular risk, patients with diabetes and MetSyn often do not reach lipid targets.¹⁷ In patients with diabetes, lowering LDL-C levels reduces the risk of a cardiovascular event by 25% to 50%.^18-23 Atorvastatin has demonstrated its efficacy for the primary prevention of cardiovascular events among patients with diabetes.^22,23

MetSyn also increases the risk of cardiovascular events and mortality.^10-13 Atorvastatin has been used effectively to achieve LDL-C goals in hypercholesterolemic patients with MetSyn.^24,25

Higher starting doses of statins are generally beneficial. This substudy of ACTFAST demonstrates that by initiating therapy at doses selected according to baseline LDL-C levels, 81% of statin-free and 60% of statin-treated subjects with diabetes and 78% of statin-free and 57% of statin-treated subjects with MetSyn achieved a target LDL-C of <100 mg/dL within 6 to 12 weeks. Among statin-treated patients, atorvastatin provided additional reduction in lipid parameters over what was achieved with the statin they had been using at baseline.

Other studies have also suggested that patients at high risk for cardiovascular events, such as those with diabetes or MetSyn, may benefit from starting therapy at a higher dose of atorvastatin.^14,15,26,27 In the New Atorvastatin Starting Doses: A Comparison (NASDAC) study, patients were randomized to receive various starting doses of atorvastatin, regardless of their baseline LDL-C value.²⁶ The proportion of patients with CHD or a CHD-equivalent (of whom 150 had diabetes) who achieved LDL-C target (<100 mg/dL) with 10, 20, 40, and 80 mg/d was 47%, 66%, 81% and 80%, respectively, demonstrating that a higher starting dose is required to achieve target.

However, lower doses may work depending on LDL-C levels. In contrast to NASDAC, statin-free patients with diabetes or MetSyn in ACTFAST showed better results on 10- and 20-mg doses, because baseline LDL-C was taken into account. The Atorvastatin Goal Achievement Across Risk Levels (ATGOAL) study used a design similar to ACTFAST, assigning patients with dyslipidemia to starting doses of atorvastatin for 8 weeks, at 10, 20, 40, or 80 mg, based on their CHD risk category and the magnitude of LDL-C reduction necessary to reach lipid targets.²⁷ Of the 1298 patients, 705 were at high CHD risk (43.8% with diabetes), and 81.1% of these high-risk patients achieved an LDL-C <100 mg/dL.

No safety issues arose when initiating atorvastatin at higher doses in patients with diabetes or MetSyn. The incidence of clinically elevated AST, ALT, or CK levels in ACTFAST was low and comparable to that reported in meta-analyses (0.96%).^28,29

Benefits of our dosing algorithm seem clear. Aggressive treatment with atorvastatin across the dose range improves LDL-C target achievement compared with usual care,^30,31 and current NCEP-III recommendations support the use of a higher initial dose in patients requiring large LDL-C reductions.¹ Atorva-statin is approved in many countries at starting doses ranging from 10 to 40 mg, with a titration to 80 mg, if needed, to achieve LDL-C target. ACTFAST suggests that, in patients with diabetes or MetSyn, initiation of atorvastatin at a dose appropriate for the required level of LDL-C reduction would facilitate achievement of LDL-C targets.

One meta-analysis of trials demonstrated that a 10-mg/dL reduction in LDL-C could result in a 5.4% reduction in major vascular events and a 3.1% reduction in all-cause mortality over 5 years.³² In our study, patients with diabetes or MetSyn experienced reductions in LDL-C of approximately 57 mg/dL, which, if maintained over 5 years, could be expected to translate into reductions of 30% in major vascular events and 17% in mortality. Therefore, a regimen that allows a larger number of high-risk patients to achieve substantial reductions in LDL-C levels quickly could significantly improve cardiovascular outcomes.

Limitations of our study include the fact that the trial was not blinded, the size of the dosing groups was unequal, and there was no control group. However, it is unlikely that reduction of LDL-C was due to chance. Also, this study was not designed to investigate the effect of lowering LDL-C on the incidence of cardiovascular events.

Correspondence
Lawrence A. Leiter, MD, University of Toronto, St. Michael's Hospital, 61 Queen St. E.,#6121Q, Toronto, Ontario, Canada. M5C 2T2; [email protected]

How many of your patients with type 2 diabetes or metabolic syndrome have a low-density lipoprotein cholesterol (LDL-C) level below the target of 100 mg/dL? Your answer, undoubtedly, is not enough of them. The good news we report in this article is that you can safely achieve the target more often, within 6 to 12 weeks, using a simple algorithm that helps you determine the optimal starting dose of a statin.

Good reason for concern. Individuals with coronary heart disease (CHD) or CHD risk equivalents such as diabetes have the highest cardiovascular risk and, according to the National Cholesterol Education Program (NCEP) III and other guidelines, must aim for the lowest target levels of LDL-C.¹ As the number of cardiovascular risk factors increases in a population, the percentage of patients reaching targets decreases^2,3 —to as low as 37% among those at highest risk.² The international Analysis and Understanding of Diabetes and Dyslipidaemia: Improving Treatment (AUDIT) survey found that out of all patients with type 2 diabetes being treated, only 54% achieved target.⁴

Type 2 diabetes purportedly imparts a cardiovascular risk comparable to that of a prior cardiovascular event.^1,5-7 Moreover, the outcome of such events in patients with diabetes is worse than in patients without diabetes, with approximately 7 out of 10 patients dying from the event or its complications.^7-9

The metabolic syndrome (MetSyn) also increases risk of cardiovascular events and mortality, even in individuals without diabetes or CHD.^10-13 In 1 study, the risks of all-cause and cardiovascular mortality in patients with MetSyn were 1.38 to 1.44 and 2.26 to 2.78, respectively, compared with those who did not have MetSyn.¹²

The algorithm we describe in this article was developed from results of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) trials. These trials were designed to assess whether, according to the degree of reduction required in LDL-C, an optimal starting dose of atorvastatin could be identified so that patients would achieve LDL-C targets quickly, with no change in the dose or with just one titration step, and regardless of statin use at baseline.

The main results of ACTFAST 1 and 2 have been published elsewhere.^14,15 We report specifically on a prespecified analysis of pooled results in the subset of patients with diabetes or MetSyn.

Methods

Patient population

We extracted the study population from prespecified pooling of data from ACTFAST 1 and 2,^14,15 which were 12-week, multicenter, prospective, open-label trials that used the same protocol. A full description of inclusion and exclusion criteria for ACTFAST has been published elsewhere.^14,15

Briefly, subjects were either statin-free or statin-treated at baseline, had CHD or a CHD equivalent, had an LDL-C level between 100 and 220 mg/dL (2.6-5.7 mmol/L) and triglycerides =600 mg/dL (6.8 mmol/L), and were willing to follow a recommended diet.

We excluded patients if they had used other lipid-lowering therapy in the prior 2 months (except for statins in the statin-treated study arm) or if they were receiving >40 mg/d of any statin. Patients taking atorvastatin at screening were excluded because the study's goal was to assess the benefits of switching over to a flexible starting dose of atorvastatin. We defined diabetes and MetSyn according to the American Diabetes Association criteria¹⁶ and the NCEP 2001 criteria,¹ respectively.

Doses reflected LDL-C baseline-target gap and prior statin use

If patients were statin free at baseline, we assigned them to 6 weeks of treatment with atorvastatin, at 10, 20, 40, or 80 mg/d, according to their baseline LDL-C level ( FIGURE 1 ). For patients who had been taking a statin at screening, starting doses of atorvastatin for each LDL-C increment were doubled.

If patients did not reach LDL-C targets at the end of 6 weeks, we titrated their regimen to the next higher dose for an additional 6 weeks. Patients initially allocated to receive atorvastatin at 80 mg who did not reach LDL-C targets continued at that dose, and we added a more intense therapeutic lifestyle intervention (NCEP II step 2 diet).¹

We obtained blood samples at baseline screening, week 6, and week 12, to measure 12-hour fasting serum lipid profiles and to make routine safety assessments (hematology and chemistry). Patients received dietary counseling at all visits.

The ACTFAST protocol and amendments were approved by appropriately constituted central or local institutional review boards, and all patients gave written informed consent.

FIGURE 1
How treatment doses were determined

Statin-free patients received a specified dose of atorvastatin according to their baseline low-density lipoprotein cholesterol (LDL-C) level. Patients who had been treated with another statin at screening received atorvastatin at a dose double that given to statin-free patients with equivalent LDL-C levels, for a maximum dose of 80 mg.

Primary efficacy outcome: LDL-C levels of <100 mg/dL

The primary efficacy outcome was the proportion of patients with either diabetes or MetSyn achieving NCEP Adult Treatment Panel-III target LDL-C levels of <100 mg/dL (<2.6 mmol/L) after 12 weeks of treatment.¹ Secondary efficacy parameters were described in ACTFAST 1.¹⁴

We analyzed data according to intention-to-treat (ITT), using the last observation carried forward (LOCF) for missing data. The ITT population consisted of all patients who took at least 1 dose of study medication, and had at least 1 subsequent assessment.

Results

Between January 2003 and February 2004, 3634 subjects were screened for ACTFAST 1 and 2, and 2717 patients were enrolled from 12 countries (Canada, Greece, Hungary, Ireland, Italy, Poland, Portugal, Russia, Slovakia, Spain, Switzerland, and the United Kingdom). Ethnicity was recorded for about 80% of patients; more than 90% were Caucasian.

Diabetes

The ITT population included 1024 patients with diabetes, of whom 97% had type 2 diabetes and 73% were statin-free ( TABLE 1 ). Baseline laboratory parameters are available online, in TABLE W1 .

After 12 weeks of treatment, 81% (95% confidence interval [CI], 77.8%-83.5%) of statin-free and 60% (95% CI, 53.9%-65.4%) of statin-treated patients with diabetes achieved LDLC target of <100 mg/dL ( FIGURE 2 ). In contrast, among patients without diabetes (n=1693), 77% (95% CI, 73.9%-79.3%) of statin-free and 59% (95% CI, 55.4%-62.5%) of statin-treated patients achieved target.

For diabetes patients, mean percent reductions in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C and apolipoprotein B (apo B) were significant vs baseline for all doses in both statin-free and statin-treated subjects ( TABLE 2 ). Significant increases in HDL-C were seen only with the 10- and 80-mg doses in statin-free patients.

FIGURE 2
Patients who achieved an LDL-C level of <100 mg/dL
after receiving 12 weeks of atorvastatin

TABLE 1
Demographic profiles of patients with diabetes or metabolic syndrome
(This is an expanded version of the table that appeared in print.)

TABLE 2
Mean percent change (95% CI) in lipid levels from baseline when patients with diabetes or metabolic syndrome took atorvastatin
(This is an expanded version of the table that appeared in print.)

Metabolic syndrome

The ITT population included 1251 patients with MetSyn, of whom 56% also had diabetes and 67% were statin-free ( TABLE 1 ). Baseline laboratory parameters are in TABLE W1 .

After 12 weeks of treatment, 78% (95% CI, 74.9%-80.5%) of statin-free and 57% (95% CI, 52.5%-62.1%) of statin-treated patients achieved LDL-C target of <100 mg/dL ( FIGURE 2 ). Among patients without MetSyn (n=1454), 79% (95% CI, 76.2%-81.7%) of statin-free and 61% (95% CI, 56.8%-64.6%) of statin-treated patients achieved target. (Because of missing data, the presence or absence of MetSyn could not be confirmed in 12 patients.)

Mean percent reductions for MetSyn patients in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C, and apo B were significant vs baseline for all doses in both statin-free and statin-treated patients ( TABLE 2 ). HDL-C increased significantly in the 10- and 20-mg statin-free groups and in the 40-mg statin-treated group.

Treatment was well tolerated

The incidences of treatment-related adverse events were similar in all patient groups, at around 10%. Most events were mild to moderate, with severe events reported in only 0.5% and 0.8% of patients with diabetes and MetSyn, respectively. Incidences of treatment-related musculoskeletal adverse events were 1.9% and 2%, respectively, in patients with and without diabetes; and were 1.7% and 2.3% in patients with and without MetSyn.

The incidence of elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times and creatine kinase (CK) >10 times the upper limit of normal were 1.1% and 0.1%, respectively, for patients with diabetes, and 0.9% and 0.08% for those with MetSyn, which did not differ from those of patients without diabetes (1.2% and 0%, respectively) or MetSyn (1.3% and 0%, respectively).

TABLE W1
Baseline lipid values for patients with diabetes or metabolic syndrome (mean ± SD)

Discussion

Despite their increased cardiovascular risk, patients with diabetes and MetSyn often do not reach lipid targets.¹⁷ In patients with diabetes, lowering LDL-C levels reduces the risk of a cardiovascular event by 25% to 50%.^18-23 Atorvastatin has demonstrated its efficacy for the primary prevention of cardiovascular events among patients with diabetes.^22,23

MetSyn also increases the risk of cardiovascular events and mortality.^10-13 Atorvastatin has been used effectively to achieve LDL-C goals in hypercholesterolemic patients with MetSyn.^24,25

Higher starting doses of statins are generally beneficial. This substudy of ACTFAST demonstrates that by initiating therapy at doses selected according to baseline LDL-C levels, 81% of statin-free and 60% of statin-treated subjects with diabetes and 78% of statin-free and 57% of statin-treated subjects with MetSyn achieved a target LDL-C of <100 mg/dL within 6 to 12 weeks. Among statin-treated patients, atorvastatin provided additional reduction in lipid parameters over what was achieved with the statin they had been using at baseline.

Other studies have also suggested that patients at high risk for cardiovascular events, such as those with diabetes or MetSyn, may benefit from starting therapy at a higher dose of atorvastatin.^14,15,26,27 In the New Atorvastatin Starting Doses: A Comparison (NASDAC) study, patients were randomized to receive various starting doses of atorvastatin, regardless of their baseline LDL-C value.²⁶ The proportion of patients with CHD or a CHD-equivalent (of whom 150 had diabetes) who achieved LDL-C target (<100 mg/dL) with 10, 20, 40, and 80 mg/d was 47%, 66%, 81% and 80%, respectively, demonstrating that a higher starting dose is required to achieve target.

However, lower doses may work depending on LDL-C levels. In contrast to NASDAC, statin-free patients with diabetes or MetSyn in ACTFAST showed better results on 10- and 20-mg doses, because baseline LDL-C was taken into account. The Atorvastatin Goal Achievement Across Risk Levels (ATGOAL) study used a design similar to ACTFAST, assigning patients with dyslipidemia to starting doses of atorvastatin for 8 weeks, at 10, 20, 40, or 80 mg, based on their CHD risk category and the magnitude of LDL-C reduction necessary to reach lipid targets.²⁷ Of the 1298 patients, 705 were at high CHD risk (43.8% with diabetes), and 81.1% of these high-risk patients achieved an LDL-C <100 mg/dL.

No safety issues arose when initiating atorvastatin at higher doses in patients with diabetes or MetSyn. The incidence of clinically elevated AST, ALT, or CK levels in ACTFAST was low and comparable to that reported in meta-analyses (0.96%).^28,29

Benefits of our dosing algorithm seem clear. Aggressive treatment with atorvastatin across the dose range improves LDL-C target achievement compared with usual care,^30,31 and current NCEP-III recommendations support the use of a higher initial dose in patients requiring large LDL-C reductions.¹ Atorva-statin is approved in many countries at starting doses ranging from 10 to 40 mg, with a titration to 80 mg, if needed, to achieve LDL-C target. ACTFAST suggests that, in patients with diabetes or MetSyn, initiation of atorvastatin at a dose appropriate for the required level of LDL-C reduction would facilitate achievement of LDL-C targets.

One meta-analysis of trials demonstrated that a 10-mg/dL reduction in LDL-C could result in a 5.4% reduction in major vascular events and a 3.1% reduction in all-cause mortality over 5 years.³² In our study, patients with diabetes or MetSyn experienced reductions in LDL-C of approximately 57 mg/dL, which, if maintained over 5 years, could be expected to translate into reductions of 30% in major vascular events and 17% in mortality. Therefore, a regimen that allows a larger number of high-risk patients to achieve substantial reductions in LDL-C levels quickly could significantly improve cardiovascular outcomes.

Limitations of our study include the fact that the trial was not blinded, the size of the dosing groups was unequal, and there was no control group. However, it is unlikely that reduction of LDL-C was due to chance. Also, this study was not designed to investigate the effect of lowering LDL-C on the incidence of cardiovascular events.

Correspondence
Lawrence A. Leiter, MD, University of Toronto, St. Michael's Hospital, 61 Queen St. E.,#6121Q, Toronto, Ontario, Canada. M5C 2T2; [email protected]

Could a child’s suicide have been prevented?

THE PATIENT. A 9-year-old boy was undergoing psychiatric treatment.

CASE FACTS. A psychiatrist prescribed bupropion. The child committed suicide.

THE PARENTS’ CLAIM. The psychiatrist was negligent because he did not diagnose suicidal behavior during the initial visit and prescribed bupropion without proper warnings and follow-up.

THE DOCTOR’S DEFENSE. He did not receive information from the patient’s family that would have indicated suicidal behavior, bupropion was an appropriate treatment and was unrelated to the suicide, the family received proper warnings about the drug, and the suicide was unforeseeable.

Submit your verdict and find out how the court ruled and see how your colleagues voted in August’s Malpractice Minute. Click on “Have more to say about this topic?” to comment.

Could a child’s suicide have been prevented?

THE PATIENT. A 9-year-old boy was undergoing psychiatric treatment.

CASE FACTS. A psychiatrist prescribed bupropion. The child committed suicide.

THE PARENTS’ CLAIM. The psychiatrist was negligent because he did not diagnose suicidal behavior during the initial visit and prescribed bupropion without proper warnings and follow-up.

THE DOCTOR’S DEFENSE. He did not receive information from the patient’s family that would have indicated suicidal behavior, bupropion was an appropriate treatment and was unrelated to the suicide, the family received proper warnings about the drug, and the suicide was unforeseeable.

Submit your verdict and find out how the court ruled and see how your colleagues voted in August’s Malpractice Minute. Click on “Have more to say about this topic?” to comment.

Could a child’s suicide have been prevented?

THE PATIENT. A 9-year-old boy was undergoing psychiatric treatment.

CASE FACTS. A psychiatrist prescribed bupropion. The child committed suicide.

THE PARENTS’ CLAIM. The psychiatrist was negligent because he did not diagnose suicidal behavior during the initial visit and prescribed bupropion without proper warnings and follow-up.

THE DOCTOR’S DEFENSE. He did not receive information from the patient’s family that would have indicated suicidal behavior, bupropion was an appropriate treatment and was unrelated to the suicide, the family received proper warnings about the drug, and the suicide was unforeseeable.

Submit your verdict and find out how the court ruled and see how your colleagues voted in August’s Malpractice Minute. Click on “Have more to say about this topic?” to comment.

The Centers for Disease Control and Prevention (CDC) has made 2 significant changes to its annual recommendations for the prevention of influenza during the 2008-2009 flu season:¹

1. Annual vaccination is now recommended for all children ages 6 months through 18 years. (Last year, universal influenza vaccination was recommended only for children ages 6 months through 4 years.)
2. The live attenuated influenza vaccine (LAIV) can now be used starting at 2 years of age.

Vaccinate older children

The CDC now recommends that 5- to 18-year-olds receive the influenza vaccine annually, and that this routine vaccination start as soon as possible, but no later than the 2009-2010 flu season. In other words, if routine vaccination can be achieved this year it is encouraged, but the CDC recognizes that it may not be possible to achieve in some settings until next year.

If family physicians do not incorporate routine vaccination for those ages 5 to 18 this year, they should still provide it for those in this age group who are at high risk for influenza complications, including those who:

• are on long-term aspirin therapy;
• have chronic pulmonary (including asthma), cardiovascular, renal, hepatic, hematological, or metabolic disorders;
• are immunosuppressed; or
• have disorders that alter respiratory functions or the handling of respiratory secretions.

Children who live in households with others who are at higher risk (children who are <5 years old, adults >50 years, and anyone with a medical condition that places him or her at high risk for severe influenza complications) should also be vaccinated.

LAIV is an option for even younger kids

Last year, the LAIV vaccine was licensed for children starting at age 5. Now, the LAIV can be given to healthy children starting at age 2, as well as to adolescents and adults through age 49. TABLE 1 compares the LAIV with the trivalent influenza vaccine (TIV).

Because LAIV is an attenuated live virus vaccine, some children should not receive it, including those younger than 5 years of age with reactive airway disease (recurrent wheezing or recent wheezing); those with a medical condition that places them at high risk of influenza complications; and those younger than 2 years of age. The TIV can be used in these children, starting at 6 months of age.

Regardless of whether a child receives LAIV or TIV, those younger than 9 years of age who are receiving influenza vaccine for the first time should receive 2 doses 4 weeks apart. If a child received only 1 dose in the first year, the following year he or she should receive 2 doses 4 weeks apart.

TABLE 1
LAIV vs TIV: How the 2 compare

Coverage rates still need to improve

Influenza vaccine and antiviral agents continue to be underutilized. TABLE 2 lists estimated coverage with influenza vaccine for specific groups for whom immunization is recommended. It is particularly important that coverage rates for health care workers—which remain below 50%—be improved. Health care workers are at high risk of exposure to influenza and pose a risk of disease transmission to their families, other staff members, and patients. Family physicians should ensure that they and their staff are vaccinated each year.

Missed opportunities. Many patients for whom influenza vaccine is recommended fail to receive the vaccine because of missed opportunities. Physicians should offer the vaccine starting in October (or as soon as the vaccine supply allows) and continue to offer and encourage it through the entire flu season. Peak influenza activity can occur as late as April and May and occurs after February on average of 1 in every 5 years.

TABLE 2
Immunization is recommended, but what were the coverage rates?*

Autism concerns persist among parents

Despite clear scientific evidence that neither vaccines nor thimerosal preservative cause autism, some parents remain concerned. Some states have passed laws prohibiting the use of any thimerosal-containing vaccines and some parents may request thimerosal-free vaccines. TABLE 3 lists all the influenza vaccines and their thimerosal content.

TABLE 3
Which vaccines contain thimerosal—and how much?

Make use of antivirals

Two antiviral medications are licensed and approved for the treatment and prevention of influenza: oseltamivir (Tamiflu) and zanamivir (Relenza). Two others (amantadine and rimantadine) are licensed but not currently recommended due to the high rates of resistance that influenza has developed against them.

Oseltamivir is approved for the treatment and prophylaxis of influenza starting at 1 year of age.

Zanamivir is approved for the treatment of influenza starting at 7 years of age and for prophylaxis starting at 5 years of age.

Treatment, if started within 48 hours of symptom onset, reduces the severity and length of infection and the length of infectiousness. Antiviral prophylaxis should be considered when there is increased influenza activity for those listed in TABLE 4.

TABLE 4
Increased flu activity in the community? Consider antiviral prophylaxis

Every bit helps

Each year, influenza kills, on average, 36,000 Americans and hospitalizes another 200,000. Much of this morbidity and mortality could be avoided with full utilization of influenza vaccines and antiviral medications. You can contribute to improved public health by assuring that your patients and staff are fully immunized, that office infection control practices are adhered to, and that antiviral prophylaxis is used when indicated.

The Centers for Disease Control and Prevention (CDC) has made 2 significant changes to its annual recommendations for the prevention of influenza during the 2008-2009 flu season:¹

1. Annual vaccination is now recommended for all children ages 6 months through 18 years. (Last year, universal influenza vaccination was recommended only for children ages 6 months through 4 years.)
2. The live attenuated influenza vaccine (LAIV) can now be used starting at 2 years of age.

Vaccinate older children

The CDC now recommends that 5- to 18-year-olds receive the influenza vaccine annually, and that this routine vaccination start as soon as possible, but no later than the 2009-2010 flu season. In other words, if routine vaccination can be achieved this year it is encouraged, but the CDC recognizes that it may not be possible to achieve in some settings until next year.

If family physicians do not incorporate routine vaccination for those ages 5 to 18 this year, they should still provide it for those in this age group who are at high risk for influenza complications, including those who:

• are on long-term aspirin therapy;
• have chronic pulmonary (including asthma), cardiovascular, renal, hepatic, hematological, or metabolic disorders;
• are immunosuppressed; or
• have disorders that alter respiratory functions or the handling of respiratory secretions.

Children who live in households with others who are at higher risk (children who are <5 years old, adults >50 years, and anyone with a medical condition that places him or her at high risk for severe influenza complications) should also be vaccinated.

LAIV is an option for even younger kids

Last year, the LAIV vaccine was licensed for children starting at age 5. Now, the LAIV can be given to healthy children starting at age 2, as well as to adolescents and adults through age 49. TABLE 1 compares the LAIV with the trivalent influenza vaccine (TIV).

Because LAIV is an attenuated live virus vaccine, some children should not receive it, including those younger than 5 years of age with reactive airway disease (recurrent wheezing or recent wheezing); those with a medical condition that places them at high risk of influenza complications; and those younger than 2 years of age. The TIV can be used in these children, starting at 6 months of age.

Regardless of whether a child receives LAIV or TIV, those younger than 9 years of age who are receiving influenza vaccine for the first time should receive 2 doses 4 weeks apart. If a child received only 1 dose in the first year, the following year he or she should receive 2 doses 4 weeks apart.

TABLE 1
LAIV vs TIV: How the 2 compare

Coverage rates still need to improve

Influenza vaccine and antiviral agents continue to be underutilized. TABLE 2 lists estimated coverage with influenza vaccine for specific groups for whom immunization is recommended. It is particularly important that coverage rates for health care workers—which remain below 50%—be improved. Health care workers are at high risk of exposure to influenza and pose a risk of disease transmission to their families, other staff members, and patients. Family physicians should ensure that they and their staff are vaccinated each year.

Missed opportunities. Many patients for whom influenza vaccine is recommended fail to receive the vaccine because of missed opportunities. Physicians should offer the vaccine starting in October (or as soon as the vaccine supply allows) and continue to offer and encourage it through the entire flu season. Peak influenza activity can occur as late as April and May and occurs after February on average of 1 in every 5 years.

TABLE 2
Immunization is recommended, but what were the coverage rates?*

Autism concerns persist among parents

Despite clear scientific evidence that neither vaccines nor thimerosal preservative cause autism, some parents remain concerned. Some states have passed laws prohibiting the use of any thimerosal-containing vaccines and some parents may request thimerosal-free vaccines. TABLE 3 lists all the influenza vaccines and their thimerosal content.

TABLE 3
Which vaccines contain thimerosal—and how much?

Make use of antivirals

Two antiviral medications are licensed and approved for the treatment and prevention of influenza: oseltamivir (Tamiflu) and zanamivir (Relenza). Two others (amantadine and rimantadine) are licensed but not currently recommended due to the high rates of resistance that influenza has developed against them.

Oseltamivir is approved for the treatment and prophylaxis of influenza starting at 1 year of age.

Zanamivir is approved for the treatment of influenza starting at 7 years of age and for prophylaxis starting at 5 years of age.

Treatment, if started within 48 hours of symptom onset, reduces the severity and length of infection and the length of infectiousness. Antiviral prophylaxis should be considered when there is increased influenza activity for those listed in TABLE 4.

TABLE 4
Increased flu activity in the community? Consider antiviral prophylaxis

Every bit helps

Each year, influenza kills, on average, 36,000 Americans and hospitalizes another 200,000. Much of this morbidity and mortality could be avoided with full utilization of influenza vaccines and antiviral medications. You can contribute to improved public health by assuring that your patients and staff are fully immunized, that office infection control practices are adhered to, and that antiviral prophylaxis is used when indicated.

The Centers for Disease Control and Prevention (CDC) has made 2 significant changes to its annual recommendations for the prevention of influenza during the 2008-2009 flu season:¹

1. Annual vaccination is now recommended for all children ages 6 months through 18 years. (Last year, universal influenza vaccination was recommended only for children ages 6 months through 4 years.)
2. The live attenuated influenza vaccine (LAIV) can now be used starting at 2 years of age.

Vaccinate older children

The CDC now recommends that 5- to 18-year-olds receive the influenza vaccine annually, and that this routine vaccination start as soon as possible, but no later than the 2009-2010 flu season. In other words, if routine vaccination can be achieved this year it is encouraged, but the CDC recognizes that it may not be possible to achieve in some settings until next year.

If family physicians do not incorporate routine vaccination for those ages 5 to 18 this year, they should still provide it for those in this age group who are at high risk for influenza complications, including those who:

• are on long-term aspirin therapy;
• have chronic pulmonary (including asthma), cardiovascular, renal, hepatic, hematological, or metabolic disorders;
• are immunosuppressed; or
• have disorders that alter respiratory functions or the handling of respiratory secretions.

Children who live in households with others who are at higher risk (children who are <5 years old, adults >50 years, and anyone with a medical condition that places him or her at high risk for severe influenza complications) should also be vaccinated.

LAIV is an option for even younger kids

Last year, the LAIV vaccine was licensed for children starting at age 5. Now, the LAIV can be given to healthy children starting at age 2, as well as to adolescents and adults through age 49. TABLE 1 compares the LAIV with the trivalent influenza vaccine (TIV).

Because LAIV is an attenuated live virus vaccine, some children should not receive it, including those younger than 5 years of age with reactive airway disease (recurrent wheezing or recent wheezing); those with a medical condition that places them at high risk of influenza complications; and those younger than 2 years of age. The TIV can be used in these children, starting at 6 months of age.

Regardless of whether a child receives LAIV or TIV, those younger than 9 years of age who are receiving influenza vaccine for the first time should receive 2 doses 4 weeks apart. If a child received only 1 dose in the first year, the following year he or she should receive 2 doses 4 weeks apart.

TABLE 1
LAIV vs TIV: How the 2 compare

Coverage rates still need to improve

Influenza vaccine and antiviral agents continue to be underutilized. TABLE 2 lists estimated coverage with influenza vaccine for specific groups for whom immunization is recommended. It is particularly important that coverage rates for health care workers—which remain below 50%—be improved. Health care workers are at high risk of exposure to influenza and pose a risk of disease transmission to their families, other staff members, and patients. Family physicians should ensure that they and their staff are vaccinated each year.

Missed opportunities. Many patients for whom influenza vaccine is recommended fail to receive the vaccine because of missed opportunities. Physicians should offer the vaccine starting in October (or as soon as the vaccine supply allows) and continue to offer and encourage it through the entire flu season. Peak influenza activity can occur as late as April and May and occurs after February on average of 1 in every 5 years.

TABLE 2
Immunization is recommended, but what were the coverage rates?*

Autism concerns persist among parents

Despite clear scientific evidence that neither vaccines nor thimerosal preservative cause autism, some parents remain concerned. Some states have passed laws prohibiting the use of any thimerosal-containing vaccines and some parents may request thimerosal-free vaccines. TABLE 3 lists all the influenza vaccines and their thimerosal content.

TABLE 3
Which vaccines contain thimerosal—and how much?

Make use of antivirals

Two antiviral medications are licensed and approved for the treatment and prevention of influenza: oseltamivir (Tamiflu) and zanamivir (Relenza). Two others (amantadine and rimantadine) are licensed but not currently recommended due to the high rates of resistance that influenza has developed against them.

Oseltamivir is approved for the treatment and prophylaxis of influenza starting at 1 year of age.

Zanamivir is approved for the treatment of influenza starting at 7 years of age and for prophylaxis starting at 5 years of age.

Treatment, if started within 48 hours of symptom onset, reduces the severity and length of infection and the length of infectiousness. Antiviral prophylaxis should be considered when there is increased influenza activity for those listed in TABLE 4.

TABLE 4
Increased flu activity in the community? Consider antiviral prophylaxis

Every bit helps

Each year, influenza kills, on average, 36,000 Americans and hospitalizes another 200,000. Much of this morbidity and mortality could be avoided with full utilization of influenza vaccines and antiviral medications. You can contribute to improved public health by assuring that your patients and staff are fully immunized, that office infection control practices are adhered to, and that antiviral prophylaxis is used when indicated.

Dr. Giesler reports that he serves on the speaker’s bureau for Ethicon Endo-Surgery. Dr. Vyas has no financial relationships relevant to this article.

CASE: Probable adhesions. Is laparoscopy practical?

A 54-year-old woman complains of perimenopausal bleeding that has not been controlled by hormone therapy, as well as increasing pelvic pain that has caused her to miss work. She wants you to perform hysterectomy to end these problems once and for all.

Aside from these complaints, her history is unremarkable except for a laparotomy at 13 years for a ruptured appendix. Her Pap smear, endometrial biopsy, and pelvic sonogram are negative.

Is she a candidate for laparoscopic hysterectomy?

A patient such as this one, who has a history of laparotomy, is likely to have extensive intra-abdominal adhesions. This pathology increases the risk of bowel injury during surgery—whether it is performed via laparotomy or laparoscopy.

The ability to simplify laparoscopic hysterectomy in a woman who has extensive adhesions requires an understanding of the ways in which adhesions form—in order to lyse them skillfully and avoid creating further adhesions. It also requires special techniques to enter the abdomen, identify the site of attachment, separate adhered structures, and conclude the hysterectomy. Attention to the type of energy that is used also is important.

In this article, we describe these techniques and considerations.

In Part 1 of this article, we discussed techniques that facilitate laparoscopic hysterectomy in a woman who has a large uterus.

Don’t overlook preoperative discussion, preparation

The patient needs to understand the risks and benefits of laparoscopic hysterectomy, particularly when extensive adhesions are likely, as well as the fact that it may be necessary to convert the procedure to laparotomy if the laparoscopic approach proves too difficult. She also needs to understand that conversion to laparotomy does not represent a failure of the procedure but an aim for greater safety.

Because bowel injury is a real risk when the patient has extensive adhesions, mechanical bowel preparation is important. Choose the regimen preferred by the colorectal surgeon likely to be consulted if intraoperative injury occurs.

The operating room (OR) and anesthesia staffs also need to be prepared, and the patient should be positioned for optimal access in the OR. These and other preoperative steps are described in Part 1 of this article and remain the same for the patient who has extensive intra-abdominal adhesions.

How adhesions form

When the peritoneum is injured, a fibrinous exudate develops, causing adjacent tissues to stick together. Normal peritoneum immediately initiates a process to break down this exudate, but traumatized peritoneum has limited ability to do so. As a result, a permanent adhesion can form in as few as 5 to 8 days.^1,2

Pelvic inflammatory disease and intraperitoneal blood associated with distant endometriosis implants are well known causes of abdominal adhesions; others are listed in the TABLE.

TABLE

7 causes of intra-abdominal adhesions

The challenge of safe entry

During laparotomy, adhesions can make it difficult to enter the abdomen. The same is true—but more so—for laparoscopic entry. The distortion caused by adhesions can lead to inadvertent injury to blood vessels, bowel, and bladder even in the best surgical hands. An attempt to lyse adhesions laparoscopically often prolongs the surgical procedure and increases the risk of visceral injury, bleeding, and fistula.¹

In more than 80% of patients experiencing injury during major abdominal surgery, the injury is associated with omental adhesions to the previous abdominal wall incision, and more than 50% have intestine included in the adhesion complex.¹

One study involving 918 patients who underwent laparoscopy found that 54.9% had umbilical adhesions of sufficient size to interfere with umbilical port placement.³ More important, 16% of this study group had only a single midline umbilical incision for laparoscopy before the adhesions were discovered.

The utility of Palmer’s point

Although multiple techniques have been described to minimize entry-related injury, no technique has completely eliminated the risk of inadvertent bowel or major large-vessel injury.³ In 1974, Palmer described an abdominal entry point for the Veress needle and small trocar for women who have a history of abdominal surgery.⁴ Many surgeons now consider “Palmer’s point,” in the left upper quadrant, as the safest peritoneal entry site.

Technique. After emptying the stomach of its contents using suction, insert the Veress needle into the peritoneal cavity at a point midway between the midclavicular line and the anterior axillary line, 3 cm below the costal margin (FIGURE). Advance it slowly until you hear three pops, signifying entry into the peritoneal cavity. Only minimal insertion is needed; insufflation pressure of less than 10 mm Hg indicates intraperitoneal placement of the needle tip.⁵

Once pneumoperitoneum pressure of 20 mm Hg is established, insert a 5-mm trocar perpendicular to the abdominal wall, 3 cm below the ribs, midway between the midclavicular line and the anterior axillary line.³ (There is a risk of colon injury at the splenic flexure if the entry point is further lateral.)

Inspect the abdominal cavity with the laparoscope from this access port to determine the best placement of remaining trocars under direct vision; lyse adhesions, if necessary, to perform the procedure.

FIGURE Enter the abdomen at Palmer’s point

This entry site (red dot) lies midway between the midclavicular line and the anterior axillary line, 3 cm below the costal margin. The other port sites (black dots) are described in Figure 2 in Part 1 of this article.

Success depends on careful lysis and minimal tissue injury

Adhesions in the abdomen may involve:

• omentum to peritoneum
• omentum to pelvic structures
• intestine to peritoneum
• intestine to pelvic structures.

Adhesions may be filmy and thin or dense and thick, avascular or vascular. They can be minimal, or a veritable curtain that prevents adequate visualization of the primary surgical site. When they are present, they must be managed successfully if the primary procedure is to be accomplished laparoscopically.

Successful management requires techniques to maximize adhesiolysis and minimize new adhesions or tissue injury:

• Use traction and countertraction to define the line of attachment; this is essential to separate two tissues bound by adhesions.
• Use atraumatic graspers to reduce the risk of tissue laceration.
• Avoid sharp dissection with scissors. Although this is the traditional method of lysis, it is often associated with bleeding that stains and obscures the line of dissection.
• Choose tools wisely. Electrosurgery and lasers use obliterative coagulation, working at temperatures of 150°C to 400°C to burn tissue. Blood and tissue are desiccated and oxidized, forming an eschar that covers and seals the bleeding area. Rebleeding during electrosurgery may occur when the instrument sticks to tissue and disrupts the eschar. In addition, monopolar instruments may cause undetected remote thermal injury, causing late complications.⁶ Both monopolar and bipolar techniques can also leave carbon particles during the oxidation process that become foci for future adhesions.⁷
• Consider ultrasonic energy. Unlike electrosurgery, ultrasonic energy is mechanical and works at much lower temperatures (50°C to 100°C), controlling bleeding by coaptive coagulation. The ultrasonic blade, vibrating at 55,500 Hz, disrupts and denatures protein to form a coagulum that seals small coapted vessels. When the effect is prolonged, secondary heat seals larger vessels. Ultrasonic energy involves minimal thermal spread, minimal carbon particle formation, and a cavitation effect similar to hydrodissection that helps expose the adhesive line. It creates minimal smoke, improving visibility. Because ultrasonic energy operates at a lower temperature, less char and necrotic tissue—important causes of adhesions—occur than with bipolar or monopolar electrical energy.⁷

Although different energy sources interact with human tissue using different mechanisms, clinical outcomes appear to be much the same and depend more on the skill of the individual surgeon than on the power source used. Data on this topic are limited.

Thawing the frozen pelvis

Many patients have adhesions that involve omentum or intestine that can be managed using simple laparoscopic techniques, but some have organs that are fixed in the pelvis by adhesions. In these cases, traction and countertraction techniques can be tedious and may cause inadvertent injury to critical structures or excessive bleeding that necessitates conversion to laparotomy.

A better way to approach the obliterated, or “frozen,” pelvis is to open the retroperitoneal space and identify critical structures:

• Enter the retroperitoneal space at the pelvic brim in an area free of adhesions. Identify the ureter and follow it to the bladder. This can be accomplished using hydrodissection techniques or cavitation techniques with ultrasonic energy.
• Skeletonize, coagulate, and cut the vessels once you reach the cardinal ligament and identify the ascending uterine blood supply.
• Dissect the structures of the obliterated cul de sac using standard techniques.
• Use sharp dissection for adhesiolysis. Laparoscopic blunt dissection of adhesions can lead to serosal tears and inadvertent enterotomy. Sharp dissection or mechanical energy devices are preferred to divide the tissue along the line of demarcation—but remember that monopolar and bipolar devices can cause remote thermal damage that goes undetected at the time of use.

When dissection becomes unproductive in one area, switch to another; dissection planes frequently open and demonstrate the relationships between pelvic structures and loops of bowel.⁸

Occasionally, the visceral peritoneum of the bowel is breached during adhesiolysis. If the mucosa and muscularis remain intact, denuded serosa need not be repaired. Surgical repair is necessary if mucosa is exposed, or perforation may occur.

Because most ObGyn residency programs offer limited training in management of bowel injuries, intraoperative consultation with a general surgeon may be indicated if more than a simple repair is required.⁸

CASE RESOLVED

You perform total laparoscopic hysterectomy and find multiple adhesions in the right lower quadrant, adjacent to the area of trocar insertion. Small intestine is adherent to the right lateral pelvic wall; sigmoid colon is adherent to the left pelvic wall; and the anterior fundus is adherent to the bladder peritoneal reflection, with the adhesions extending on either side to include the round ligaments.

You begin adhesiolysis in the right lower quadrant to optimize trocar movement. You transect the round ligaments in the mid-position, with dissection extended retroperitoneally on either side to the midline of the lower uterine segment; this opens access to the ascending branch of the uterine vessels. You dissect the intestine free of either pelvic sidewall along the line of demarcation.

Total blood loss is less than 25 mL. The patient is discharged 6 hours after surgery.

Dr. Giesler reports that he serves on the speaker’s bureau for Ethicon Endo-Surgery. Dr. Vyas has no financial relationships relevant to this article.

CASE: Probable adhesions. Is laparoscopy practical?

A 54-year-old woman complains of perimenopausal bleeding that has not been controlled by hormone therapy, as well as increasing pelvic pain that has caused her to miss work. She wants you to perform hysterectomy to end these problems once and for all.

Aside from these complaints, her history is unremarkable except for a laparotomy at 13 years for a ruptured appendix. Her Pap smear, endometrial biopsy, and pelvic sonogram are negative.

Is she a candidate for laparoscopic hysterectomy?

A patient such as this one, who has a history of laparotomy, is likely to have extensive intra-abdominal adhesions. This pathology increases the risk of bowel injury during surgery—whether it is performed via laparotomy or laparoscopy.

The ability to simplify laparoscopic hysterectomy in a woman who has extensive adhesions requires an understanding of the ways in which adhesions form—in order to lyse them skillfully and avoid creating further adhesions. It also requires special techniques to enter the abdomen, identify the site of attachment, separate adhered structures, and conclude the hysterectomy. Attention to the type of energy that is used also is important.

In this article, we describe these techniques and considerations.

In Part 1 of this article, we discussed techniques that facilitate laparoscopic hysterectomy in a woman who has a large uterus.

Don’t overlook preoperative discussion, preparation

The patient needs to understand the risks and benefits of laparoscopic hysterectomy, particularly when extensive adhesions are likely, as well as the fact that it may be necessary to convert the procedure to laparotomy if the laparoscopic approach proves too difficult. She also needs to understand that conversion to laparotomy does not represent a failure of the procedure but an aim for greater safety.

Because bowel injury is a real risk when the patient has extensive adhesions, mechanical bowel preparation is important. Choose the regimen preferred by the colorectal surgeon likely to be consulted if intraoperative injury occurs.

The operating room (OR) and anesthesia staffs also need to be prepared, and the patient should be positioned for optimal access in the OR. These and other preoperative steps are described in Part 1 of this article and remain the same for the patient who has extensive intra-abdominal adhesions.

How adhesions form

When the peritoneum is injured, a fibrinous exudate develops, causing adjacent tissues to stick together. Normal peritoneum immediately initiates a process to break down this exudate, but traumatized peritoneum has limited ability to do so. As a result, a permanent adhesion can form in as few as 5 to 8 days.^1,2

Pelvic inflammatory disease and intraperitoneal blood associated with distant endometriosis implants are well known causes of abdominal adhesions; others are listed in the TABLE.

TABLE

7 causes of intra-abdominal adhesions

The challenge of safe entry

During laparotomy, adhesions can make it difficult to enter the abdomen. The same is true—but more so—for laparoscopic entry. The distortion caused by adhesions can lead to inadvertent injury to blood vessels, bowel, and bladder even in the best surgical hands. An attempt to lyse adhesions laparoscopically often prolongs the surgical procedure and increases the risk of visceral injury, bleeding, and fistula.¹

In more than 80% of patients experiencing injury during major abdominal surgery, the injury is associated with omental adhesions to the previous abdominal wall incision, and more than 50% have intestine included in the adhesion complex.¹

One study involving 918 patients who underwent laparoscopy found that 54.9% had umbilical adhesions of sufficient size to interfere with umbilical port placement.³ More important, 16% of this study group had only a single midline umbilical incision for laparoscopy before the adhesions were discovered.

The utility of Palmer’s point

Although multiple techniques have been described to minimize entry-related injury, no technique has completely eliminated the risk of inadvertent bowel or major large-vessel injury.³ In 1974, Palmer described an abdominal entry point for the Veress needle and small trocar for women who have a history of abdominal surgery.⁴ Many surgeons now consider “Palmer’s point,” in the left upper quadrant, as the safest peritoneal entry site.

Technique. After emptying the stomach of its contents using suction, insert the Veress needle into the peritoneal cavity at a point midway between the midclavicular line and the anterior axillary line, 3 cm below the costal margin (FIGURE). Advance it slowly until you hear three pops, signifying entry into the peritoneal cavity. Only minimal insertion is needed; insufflation pressure of less than 10 mm Hg indicates intraperitoneal placement of the needle tip.⁵

Once pneumoperitoneum pressure of 20 mm Hg is established, insert a 5-mm trocar perpendicular to the abdominal wall, 3 cm below the ribs, midway between the midclavicular line and the anterior axillary line.³ (There is a risk of colon injury at the splenic flexure if the entry point is further lateral.)

Inspect the abdominal cavity with the laparoscope from this access port to determine the best placement of remaining trocars under direct vision; lyse adhesions, if necessary, to perform the procedure.

FIGURE Enter the abdomen at Palmer’s point

This entry site (red dot) lies midway between the midclavicular line and the anterior axillary line, 3 cm below the costal margin. The other port sites (black dots) are described in Figure 2 in Part 1 of this article.

Success depends on careful lysis and minimal tissue injury

Adhesions in the abdomen may involve:

• omentum to peritoneum
• omentum to pelvic structures
• intestine to peritoneum
• intestine to pelvic structures.

Adhesions may be filmy and thin or dense and thick, avascular or vascular. They can be minimal, or a veritable curtain that prevents adequate visualization of the primary surgical site. When they are present, they must be managed successfully if the primary procedure is to be accomplished laparoscopically.

Successful management requires techniques to maximize adhesiolysis and minimize new adhesions or tissue injury:

• Use traction and countertraction to define the line of attachment; this is essential to separate two tissues bound by adhesions.
• Use atraumatic graspers to reduce the risk of tissue laceration.
• Avoid sharp dissection with scissors. Although this is the traditional method of lysis, it is often associated with bleeding that stains and obscures the line of dissection.
• Choose tools wisely. Electrosurgery and lasers use obliterative coagulation, working at temperatures of 150°C to 400°C to burn tissue. Blood and tissue are desiccated and oxidized, forming an eschar that covers and seals the bleeding area. Rebleeding during electrosurgery may occur when the instrument sticks to tissue and disrupts the eschar. In addition, monopolar instruments may cause undetected remote thermal injury, causing late complications.⁶ Both monopolar and bipolar techniques can also leave carbon particles during the oxidation process that become foci for future adhesions.⁷
• Consider ultrasonic energy. Unlike electrosurgery, ultrasonic energy is mechanical and works at much lower temperatures (50°C to 100°C), controlling bleeding by coaptive coagulation. The ultrasonic blade, vibrating at 55,500 Hz, disrupts and denatures protein to form a coagulum that seals small coapted vessels. When the effect is prolonged, secondary heat seals larger vessels. Ultrasonic energy involves minimal thermal spread, minimal carbon particle formation, and a cavitation effect similar to hydrodissection that helps expose the adhesive line. It creates minimal smoke, improving visibility. Because ultrasonic energy operates at a lower temperature, less char and necrotic tissue—important causes of adhesions—occur than with bipolar or monopolar electrical energy.⁷

Although different energy sources interact with human tissue using different mechanisms, clinical outcomes appear to be much the same and depend more on the skill of the individual surgeon than on the power source used. Data on this topic are limited.

Thawing the frozen pelvis

Many patients have adhesions that involve omentum or intestine that can be managed using simple laparoscopic techniques, but some have organs that are fixed in the pelvis by adhesions. In these cases, traction and countertraction techniques can be tedious and may cause inadvertent injury to critical structures or excessive bleeding that necessitates conversion to laparotomy.

A better way to approach the obliterated, or “frozen,” pelvis is to open the retroperitoneal space and identify critical structures:

• Enter the retroperitoneal space at the pelvic brim in an area free of adhesions. Identify the ureter and follow it to the bladder. This can be accomplished using hydrodissection techniques or cavitation techniques with ultrasonic energy.
• Skeletonize, coagulate, and cut the vessels once you reach the cardinal ligament and identify the ascending uterine blood supply.
• Dissect the structures of the obliterated cul de sac using standard techniques.
• Use sharp dissection for adhesiolysis. Laparoscopic blunt dissection of adhesions can lead to serosal tears and inadvertent enterotomy. Sharp dissection or mechanical energy devices are preferred to divide the tissue along the line of demarcation—but remember that monopolar and bipolar devices can cause remote thermal damage that goes undetected at the time of use.

When dissection becomes unproductive in one area, switch to another; dissection planes frequently open and demonstrate the relationships between pelvic structures and loops of bowel.⁸

Occasionally, the visceral peritoneum of the bowel is breached during adhesiolysis. If the mucosa and muscularis remain intact, denuded serosa need not be repaired. Surgical repair is necessary if mucosa is exposed, or perforation may occur.

Because most ObGyn residency programs offer limited training in management of bowel injuries, intraoperative consultation with a general surgeon may be indicated if more than a simple repair is required.⁸

CASE RESOLVED

You perform total laparoscopic hysterectomy and find multiple adhesions in the right lower quadrant, adjacent to the area of trocar insertion. Small intestine is adherent to the right lateral pelvic wall; sigmoid colon is adherent to the left pelvic wall; and the anterior fundus is adherent to the bladder peritoneal reflection, with the adhesions extending on either side to include the round ligaments.

You begin adhesiolysis in the right lower quadrant to optimize trocar movement. You transect the round ligaments in the mid-position, with dissection extended retroperitoneally on either side to the midline of the lower uterine segment; this opens access to the ascending branch of the uterine vessels. You dissect the intestine free of either pelvic sidewall along the line of demarcation.

Total blood loss is less than 25 mL. The patient is discharged 6 hours after surgery.

Dr. Giesler reports that he serves on the speaker’s bureau for Ethicon Endo-Surgery. Dr. Vyas has no financial relationships relevant to this article.

CASE: Probable adhesions. Is laparoscopy practical?

A 54-year-old woman complains of perimenopausal bleeding that has not been controlled by hormone therapy, as well as increasing pelvic pain that has caused her to miss work. She wants you to perform hysterectomy to end these problems once and for all.

Aside from these complaints, her history is unremarkable except for a laparotomy at 13 years for a ruptured appendix. Her Pap smear, endometrial biopsy, and pelvic sonogram are negative.

Is she a candidate for laparoscopic hysterectomy?

A patient such as this one, who has a history of laparotomy, is likely to have extensive intra-abdominal adhesions. This pathology increases the risk of bowel injury during surgery—whether it is performed via laparotomy or laparoscopy.

The ability to simplify laparoscopic hysterectomy in a woman who has extensive adhesions requires an understanding of the ways in which adhesions form—in order to lyse them skillfully and avoid creating further adhesions. It also requires special techniques to enter the abdomen, identify the site of attachment, separate adhered structures, and conclude the hysterectomy. Attention to the type of energy that is used also is important.

In this article, we describe these techniques and considerations.

In Part 1 of this article, we discussed techniques that facilitate laparoscopic hysterectomy in a woman who has a large uterus.

Don’t overlook preoperative discussion, preparation

The patient needs to understand the risks and benefits of laparoscopic hysterectomy, particularly when extensive adhesions are likely, as well as the fact that it may be necessary to convert the procedure to laparotomy if the laparoscopic approach proves too difficult. She also needs to understand that conversion to laparotomy does not represent a failure of the procedure but an aim for greater safety.

Because bowel injury is a real risk when the patient has extensive adhesions, mechanical bowel preparation is important. Choose the regimen preferred by the colorectal surgeon likely to be consulted if intraoperative injury occurs.

The operating room (OR) and anesthesia staffs also need to be prepared, and the patient should be positioned for optimal access in the OR. These and other preoperative steps are described in Part 1 of this article and remain the same for the patient who has extensive intra-abdominal adhesions.

How adhesions form

When the peritoneum is injured, a fibrinous exudate develops, causing adjacent tissues to stick together. Normal peritoneum immediately initiates a process to break down this exudate, but traumatized peritoneum has limited ability to do so. As a result, a permanent adhesion can form in as few as 5 to 8 days.^1,2

Pelvic inflammatory disease and intraperitoneal blood associated with distant endometriosis implants are well known causes of abdominal adhesions; others are listed in the TABLE.

TABLE

7 causes of intra-abdominal adhesions

The challenge of safe entry

During laparotomy, adhesions can make it difficult to enter the abdomen. The same is true—but more so—for laparoscopic entry. The distortion caused by adhesions can lead to inadvertent injury to blood vessels, bowel, and bladder even in the best surgical hands. An attempt to lyse adhesions laparoscopically often prolongs the surgical procedure and increases the risk of visceral injury, bleeding, and fistula.¹

In more than 80% of patients experiencing injury during major abdominal surgery, the injury is associated with omental adhesions to the previous abdominal wall incision, and more than 50% have intestine included in the adhesion complex.¹

One study involving 918 patients who underwent laparoscopy found that 54.9% had umbilical adhesions of sufficient size to interfere with umbilical port placement.³ More important, 16% of this study group had only a single midline umbilical incision for laparoscopy before the adhesions were discovered.

The utility of Palmer’s point

Although multiple techniques have been described to minimize entry-related injury, no technique has completely eliminated the risk of inadvertent bowel or major large-vessel injury.³ In 1974, Palmer described an abdominal entry point for the Veress needle and small trocar for women who have a history of abdominal surgery.⁴ Many surgeons now consider “Palmer’s point,” in the left upper quadrant, as the safest peritoneal entry site.

Technique. After emptying the stomach of its contents using suction, insert the Veress needle into the peritoneal cavity at a point midway between the midclavicular line and the anterior axillary line, 3 cm below the costal margin (FIGURE). Advance it slowly until you hear three pops, signifying entry into the peritoneal cavity. Only minimal insertion is needed; insufflation pressure of less than 10 mm Hg indicates intraperitoneal placement of the needle tip.⁵

Once pneumoperitoneum pressure of 20 mm Hg is established, insert a 5-mm trocar perpendicular to the abdominal wall, 3 cm below the ribs, midway between the midclavicular line and the anterior axillary line.³ (There is a risk of colon injury at the splenic flexure if the entry point is further lateral.)

Inspect the abdominal cavity with the laparoscope from this access port to determine the best placement of remaining trocars under direct vision; lyse adhesions, if necessary, to perform the procedure.

FIGURE Enter the abdomen at Palmer’s point

This entry site (red dot) lies midway between the midclavicular line and the anterior axillary line, 3 cm below the costal margin. The other port sites (black dots) are described in Figure 2 in Part 1 of this article.

Success depends on careful lysis and minimal tissue injury

Adhesions in the abdomen may involve:

• omentum to peritoneum
• omentum to pelvic structures
• intestine to peritoneum
• intestine to pelvic structures.

Adhesions may be filmy and thin or dense and thick, avascular or vascular. They can be minimal, or a veritable curtain that prevents adequate visualization of the primary surgical site. When they are present, they must be managed successfully if the primary procedure is to be accomplished laparoscopically.

Successful management requires techniques to maximize adhesiolysis and minimize new adhesions or tissue injury:

• Use traction and countertraction to define the line of attachment; this is essential to separate two tissues bound by adhesions.
• Use atraumatic graspers to reduce the risk of tissue laceration.
• Avoid sharp dissection with scissors. Although this is the traditional method of lysis, it is often associated with bleeding that stains and obscures the line of dissection.
• Choose tools wisely. Electrosurgery and lasers use obliterative coagulation, working at temperatures of 150°C to 400°C to burn tissue. Blood and tissue are desiccated and oxidized, forming an eschar that covers and seals the bleeding area. Rebleeding during electrosurgery may occur when the instrument sticks to tissue and disrupts the eschar. In addition, monopolar instruments may cause undetected remote thermal injury, causing late complications.⁶ Both monopolar and bipolar techniques can also leave carbon particles during the oxidation process that become foci for future adhesions.⁷
• Consider ultrasonic energy. Unlike electrosurgery, ultrasonic energy is mechanical and works at much lower temperatures (50°C to 100°C), controlling bleeding by coaptive coagulation. The ultrasonic blade, vibrating at 55,500 Hz, disrupts and denatures protein to form a coagulum that seals small coapted vessels. When the effect is prolonged, secondary heat seals larger vessels. Ultrasonic energy involves minimal thermal spread, minimal carbon particle formation, and a cavitation effect similar to hydrodissection that helps expose the adhesive line. It creates minimal smoke, improving visibility. Because ultrasonic energy operates at a lower temperature, less char and necrotic tissue—important causes of adhesions—occur than with bipolar or monopolar electrical energy.⁷

Although different energy sources interact with human tissue using different mechanisms, clinical outcomes appear to be much the same and depend more on the skill of the individual surgeon than on the power source used. Data on this topic are limited.

Thawing the frozen pelvis

Many patients have adhesions that involve omentum or intestine that can be managed using simple laparoscopic techniques, but some have organs that are fixed in the pelvis by adhesions. In these cases, traction and countertraction techniques can be tedious and may cause inadvertent injury to critical structures or excessive bleeding that necessitates conversion to laparotomy.

A better way to approach the obliterated, or “frozen,” pelvis is to open the retroperitoneal space and identify critical structures:

• Enter the retroperitoneal space at the pelvic brim in an area free of adhesions. Identify the ureter and follow it to the bladder. This can be accomplished using hydrodissection techniques or cavitation techniques with ultrasonic energy.
• Skeletonize, coagulate, and cut the vessels once you reach the cardinal ligament and identify the ascending uterine blood supply.
• Dissect the structures of the obliterated cul de sac using standard techniques.
• Use sharp dissection for adhesiolysis. Laparoscopic blunt dissection of adhesions can lead to serosal tears and inadvertent enterotomy. Sharp dissection or mechanical energy devices are preferred to divide the tissue along the line of demarcation—but remember that monopolar and bipolar devices can cause remote thermal damage that goes undetected at the time of use.

When dissection becomes unproductive in one area, switch to another; dissection planes frequently open and demonstrate the relationships between pelvic structures and loops of bowel.⁸

Occasionally, the visceral peritoneum of the bowel is breached during adhesiolysis. If the mucosa and muscularis remain intact, denuded serosa need not be repaired. Surgical repair is necessary if mucosa is exposed, or perforation may occur.

Because most ObGyn residency programs offer limited training in management of bowel injuries, intraoperative consultation with a general surgeon may be indicated if more than a simple repair is required.⁸

CASE RESOLVED

You perform total laparoscopic hysterectomy and find multiple adhesions in the right lower quadrant, adjacent to the area of trocar insertion. Small intestine is adherent to the right lateral pelvic wall; sigmoid colon is adherent to the left pelvic wall; and the anterior fundus is adherent to the bladder peritoneal reflection, with the adhesions extending on either side to include the round ligaments.

You begin adhesiolysis in the right lower quadrant to optimize trocar movement. You transect the round ligaments in the mid-position, with dissection extended retroperitoneally on either side to the midline of the lower uterine segment; this opens access to the ascending branch of the uterine vessels. You dissect the intestine free of either pelvic sidewall along the line of demarcation.

Total blood loss is less than 25 mL. The patient is discharged 6 hours after surgery.

The authors report no financial relationships relevant to this article.

CASE: Large fibroid uterus. Is laparoscopy feasible?

A 41-year-old woman known to have uterine fibroids consults you after two other gynecologists have recommended abdominal hysterectomy. She weighs 320 lb, stands 5 ft 2 in, and is nulliparous and sexually inactive. Pelvic ultrasonography reveals multiple fibroids approximating 18 weeks’ gestational size. Although she has hypertension and reactive airway disease, these conditions are well controlled by medication. Her Pap smear and endometrial biopsy are negative.

Because her professional commitments limit her time for recovery, she hopes to bypass abdominal hysterectomy in favor of the laparoscopic approach.

Is this desire realistic?

Twenty years have passed since Reich performed the first total laparoscopic hysterectomy,¹ but only a small percentage of hysterectomies performed in the United States utilize that approach. In 2003, 12% of 602,457 hysterectomies were done laparoscopically; the rest were performed using the abdominal or vaginal approach (66% and 22%, respectively).²

Yet laparoscopic hysterectomy has much to recommend it. Compared with abdominal hysterectomy, it involves a shorter hospital stay, less blood loss, a speedier return to normal activities, and fewer wound infections.³ Unlike vaginal hysterectomy, it also facilitates intra-abdominal inspection.

Although the opening case represents potentially difficult surgery because of the size of the uterus, the laparoscopic approach is feasible. When the uterus weighs more than 450 g, contains fibroids larger than 6 cm, or exceeds 12 to 14 cm in size,^4-7 there is an increased risk of visceral injury, bleeding necessitating transfusion, prolonged operative time, and conversion to laparotomy. This article describes techniques that simplify laparoscopic management when the uterus exceeds 14 weeks’ size. By incorporating these techniques, we have performed laparoscopic hysterectomy in uteri as large as 22 to 24 weeks’ size without increased complications.

In Part 2 of this article, we address techniques that simplify laparoscopy when extensive intra-abdominal adhesions are present.

Why do some surgeons avoid laparoscopy?

Major complications occur in approximately 5% to 6% of women who undergo total laparoscopic hysterectomy.^8,9 That is one of the reasons many surgeons who perform laparoscopic procedures revert to the more traditional vaginal or abdominal approach when faced with a potentially difficult hysterectomy. These surgeons cite uteri larger than 14 weeks’ size, extensive intra-abdominal adhesions, and morbid obesity as common indications for a more conservative approach. Others cite the limitations of working with inexperienced surgeons or residents, inadequate laparoscopic instruments, and distorted pelvic anatomy. Still others avoid laparoscopy when the patient has medical problems that preclude use of pneumoperitoneum or a steep Trendelenburg position.

In some cases, laparoscopic hysterectomy is simply not practical. In others, however, such as the presence of a large uterus, it can be achieved with attention to detail, a few key techniques, and proper counseling of the patient.

Success begins preop

All surgical decisions begin with the patient. A comprehensive preoperative discussion of pertinent management options allows both patient and surgeon to proceed with confidence. Easing the patient’s preoperative anxiety is important. It can be achieved by explaining what to expect—not only the normal recovery for laparoscopic hysterectomy, but also the expected recovery if it becomes necessary to convert to laparotomy. If the patient has clear expectations, unexpected outcomes such as conversion are better tolerated. When it comes down to a choice between the surgeon’s ego or patient safety, the patient always wins. Conversion is not failure.

Another important topic to discuss with the patient is the risk of bowel injury. Mechanical bowel preparation is not essential for every patient who undergoes laparoscopic hysterectomy, but the risk of injury to the bowel necessitating colorectal surgical assistance may be heightened in women who have a large uterus or extensive intra-abdominal adhesions. Because of this risk, mechanical bowel preparation with oral polyethylene glycol solution or sodium phosphate should be considered. Most patients prefer the latter.¹⁰

What data show about bowel preps

The literature provides conflicting messages about the effectiveness of mechanical bowel preparation in averting additional complications when bowel injury occurs. Nichols and colleagues surveyed 808 active board-certified colorectal surgeons in the United States and Canada in 1995.¹¹ All of the 471 (58%) surgeons who responded reported using some form of mechanical bowel preparation for their elective and emergency colorectal procedures.

Zmora and associates described the difficulty of designing a multicenter study to evaluate the role of mechanical bowel preparation in patient outcome.¹⁰ Of the many variables that warrant consideration, surgical technique was the single most important factor influencing surgical outcome.

In a review of evidence supporting the need for prophylactic mechanical bowel preparation prior to elective colorectal surgery, Guenaga and colleagues concluded that this practice is unsupported by the data.¹²

Bottom line. Given these data, the gynecologist wanting to practice evidence-based medicine should base his or her recommendations about bowel preparation on the preferences of the general or colorectal surgeon who will be called if a bowel injury occurs.

Don’t forget the team

After preparing the patient, prepare your support team—the operating room (OR) and anesthesia staffs. The OR staff should ensure that extra sutures, instruments, and retractors are unopened, in the room, and available in case conversion is necessary. Inform the anesthesia staff of your anticipated surgical time and potential pitfalls. Let them know you will need maximum Trendelenburg position for pelvic exposure, but remain flexible if the patient has trouble with oxygenation and ventilation. Making your anesthesiologist aware of your willingness to work together will benefit both you and your patient immensely.

Preparation continues in the OR

Appropriate patient positioning is key to successful completion of difficult laparoscopic cases. Position the patient’s buttocks several inches beyond the table break to facilitate maximal uterine manipulation, which may be needed for completion of the colpotomy.

Place the patient in the dorsal lithotomy position using Allen stirrups, with the knees flexed at a 90° angle. Keep the knees level with the hips and the hips extended neutrally.

Arm position is important to maximize room for the surgeon alongside the OR table. Space is limited when the patient’s arms are positioned on arm boards. Tucking the arms at the patient’s sides, with the antecubital fossa anterior and the palm cupping the hip, improves the surgical field and secures the patient to the OR table (FIGURE 1). Protect the elbows and hands with cushions.

Place sequential compression devices (on the calf or foot) for the duration of the procedure to minimize the risk of blood stasis and clots that sometimes develop in the legs with prolonged surgical times. Many complex laparoscopic cases last longer than 2 hours.

FIGURE 1 Positioning the patient

Tuck the arms at the patient’s sides, with the antecubital fossa anterior and the palm cupping the hip, to improve the surgical field.

Maximum Trendelenburg position is a must