Week 46 – ACCORD

“Effects of Intensive Glucose Lowering in Type 2 Diabetes”

by the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group

N Engl J Med. 2008 Jun 12;358(24):2545-59. [free full text]

We all treat type 2 diabetes mellitus (T2DM) on a daily basis, and we understand that untreated T2DM places patients at increased risk for adverse micro- and macrovascular outcomes. Prior to the 2008 ACCORD study, prospective epidemiological studies had noted a direct correlation between increased hemoglobin A1c values and increased risk of cardiovascular events. This correlation implied that treating T2DM to lower A1c levels would result in the reduction of cardiovascular risk. The ACCORD trial was the first large RCT to evaluate this specific hypothesis through comparison of events in two treatment groups – aggressive and less aggressive glucose management.

The trial enrolled patients with T2DM with A1c ≥ 7.5% and either age 40-79 with prior cardiovascular disease or age 55-79 with “anatomical evidence of significant atherosclerosis,” albuminuria, LVH, or ≥ 2 additional risk factors for cardiovascular disease (dyslipidemia, HTN, current smoker, or obesity). Notable exclusion criteria included “frequent or recent serious hypoglycemic events,” an unwillingness to inject insulin, BMI > 45, Cr > 1.5, or “other serious illness.” Patients were randomized to either intensive therapy targeting A1c to < 6.0% or to standard therapy targeting A1c 7.0-7.9%. The primary outcome was a composite first nonfatal MI or nonfatal stroke and death from cardiovascular causes. Reported secondary outcomes included all-cause mortality, severe hypoglycemia, heart failure, motor vehicle accidents in which the patient was the driver, fluid retention, and weight gain.

10,251 patients were randomized. The average age was 62, the average duration of T2DM was 10 years, and the average A1c was 8.1%. Both groups lowered their median A1c quickly, and median A1c values of the two groups separated rapidly within the first four months. (See Figure 1.) The intensive-therapy group had more exposure to antihyperglycemics of all classes. See Table 2.) Drugs were more frequently added, removed, or titrated in the intensive-therapy group (4.4 times per year versus 2.0 times per year in the standard-therapy group). At one year, the intensive-therapy group had a median A1c of 6.4% versus 7.5% in the standard-therapy group.

The primary outcome of MI/stroke/cardiovascular death occurred in 352 (6.9%) intensive-therapy patients versus 371 (7.2%) standard-therapy patients (HR 0.90, 95% CI 0.78-1.04, p = 0.16).

The trial was stopped early at a mean follow-up of 3.5 years due to increased all-cause mortality in the intensive-therapy group. 257 (5.0%) of the intensive-therapy patients died, but only 203 (4.0%) of the standard-therapy patients died (HR 1.22, 95% CI 1.01-1.46, p = 0.04). For every 95 patients treated with intensive therapy for 3.5 years, one extra patient died. Death from cardiovascular causes was also increased in the intensive-therapy group (HR 1.35, 95% CI 1.04-1.76, p = 0.02).

Regarding additional secondary outcomes, the intensive-therapy group had higher rates of hypoglycemia, weight gain, and fluid retention than the standard-therapy group. (See Table 3.) There were no group differences in rates of heart failure or motor vehicle accidents in which the patient was the driver.

Intensive glucose control of T2DM increased all-cause mortality and did not alter the risk of cardiovascular events. This harm was previously unrecognized.

The authors performed sensitivities analyses, including non-prespecified analyses, such as group differences in use of drugs like rosiglitazone, and they were unable to find an explanation for this increased mortality.

The target A1c level in T2DM remains a nuanced, patient-specific goal. Aggressive management may lead to improved microvascular outcomes, but it must be weighed against the risk of hypoglycemia. As summarized by UpToDate, while long-term data from the UKPDS suggests there may be a macrovascular benefit to aggressive glucose management early in the course of T2DM, the data from ACCORD suggest strongly that, in patients with longstanding T2DM and additional risk factors for cardiovascular disease, such management increases mortality.

The 2019 American Diabetes Association guidelines suggest that “a reasonable A1c goal for many nonpregnant adults is < 7%.” More stringent goals (< 6.5%) may be appropriate if they can be achieved without significant hypoglycemia or polypharmacy, and less stringent goals (< 8%) may be appropriate for patients “with a severe history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications…”

Of note, ACCORD also simultaneously cross-enrolled its patients in studies of intensive blood pressure management and adjunctive lipid management with fenofibrate. See this 2010 NIH press release and the links below for more information.

ACCORD Blood Pressure – NEJM, Wiki Journal Club

ACCORD Lipids – NEJM, Wiki Journal Club

Further Reading/References:
1. ACCORD @ Wiki Journal Club
2. ACCORD @ 2 Minute Medicine
3. American Diabetes Association – “Glycemic Targets.” Diabetes Care (2019).
4. “Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.” Lancet (2010).

Summary by Duncan F. Moore, MD

Week 45 – COURAGE

“Optimal Medical Therapy with or without PCI for Stable Coronary Disease”

by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Research Group

N Engl J Med. 2007 Apr 12;356(15):1503-16 [free full text]

The optimal medical management of stable coronary artery disease has been well-described. However, prior to the 2007 COURAGE trial, the role of percutaneous coronary intervention (PCI) in the initial management of stable coronary artery disease was unclear. It was known that PCI improved angina symptoms and short-term exercise performance in stable disease, but its mortality benefit and reduction of future myocardial infarction and ACS were unknown.

The trial recruited patients with stable coronary artery disease. (See paper for inclusion/exclusion criteria. Disease had to be sufficiently and objectively severe, but not too severe, and symptoms could not be sustained at the highest CCS grade.) Patients were randomized to either optimal medical management (including antiplatelet, anti-anginal, ACEi/ARB, and cholesterol-lowering therapy) and PCI or to optimal medical management alone. The primary outcome was a composite of all-cause mortality and non-fatal MI.

2287 patients were randomized. Both groups had similar baseline characteristics with the exception of a higher prevalence of proximal LAD disease in the medical-therapy group. Median duration of follow-up was 4.6 years in both groups. Death or non-fatal MI occurred in 18.4% of the PCI group and in 17.8% of the medical-therapy group (p = 0.62). Death, non-fatal MI, or stroke occurred in 20.0% of the PCI group and 19.5% of the medical-therapy group (p = 0.62). Hospitalization for ACS occurred in 12.4% of the PCI group and 11.8% of the medical-therapy group (p = 0.56). Revascularization during follow-up was performed in 21.1% of the PCI group but in 32.6% of the medical-therapy group (HR 0.60, 95% CI 0.51–0.71, p < 0.001). Finally, 66% of PCI patients were free of angina at 1-year follow-up compared with 58% of medical-therapy patients (p < 0.001). Rates were 72% and 67% at 3 years (p = 0.02) and 72% and 74% at five years (not significant).

Thus, in the initial management of stable coronary artery disease, PCI in addition to optimal medical management provided no mortality benefit over optimal medical management alone. However, initial management with PCI did provide a time-limited improvement in angina symptoms.

As the authors of COURAGE nicely summarize on page 1512, the atherosclerotic plaques of ACS and stable CAD are different. Vulnerable, ACS-prone plaques have thin caps and spread outward along the wall of the coronary artery, as opposed to stable CAD plaques, which have thick fibrous caps and are associated with inward-directed remodeling that narrows the artery lumen (and cause reliable angina symptoms and luminal narrowing on coronary angiography).

Notable limitations of this study:

      • Generalizability was limited due to the population, which was largely male, white, and 42% came from VA hospitals.
      • Drug-eluting stents were not clinically available until the last 6 months of the study, so most stents placed were bare metal.

Later meta-analyses were weakly suggestive of an association of PCI with improved all-cause mortality. It is thought that there may be a subset of patients with stable CAD who achieve a mortality benefit from PCI.

The 2017 ORBITA trial made headlines and caused sustained controversy when it demonstrated in a randomized trial that, in the context of optimal medical therapy, PCI did not increase exercise time more than did a sham PCI. Take note of the relatively savage author’s reply to commentary regarding the trial. See blog discussion here. The ORBITA-2 trial is currently underway.

The ongoing ISCHEMIA trial is both eagerly awaited and involved in a degree of controversy after a recent change in endpoints.

It is important to note that all of the above discussions assume that the patient does not have specific coronary artery anatomy (e.g. left main disease, multi-vessel disease with decreased LVEF) in which initial CABG would provide a mortality benefit. Finally, PCI should be considered in patients whose physical activity is limited by angina symptoms despite optimal medical therapy.

Further Reading:
1. COURAGE @ Wiki Journal Club
2. COURAGE @ 2 Minute Medicine
3. Canadian Cardiovascular Society grading of angina pectoris
4. ORBITA-2 @ ClinicalTrials.gov
5. ISCHEMIA @ ClinicalTrials.gov
6. Discussion re: ISCHEMIA trial changes @ CardioBrief

Summary by Duncan F. Moore, MD

Image Credit: National Institutes of Health, US Public Domain, via Wikimedia Commons