Maester’s Collection: Cushing Syndrome

  • Central obesity, arterial hypertension, proximal muscle weakness, diabetes, oligomenorrhea, hirsutism, thin skin, and ecchymosis
  • Today, obesity is common. Anti-androgenic effects of Cushing syndrome can help differentiate it from obesity
    • +LR thin skin 112
    • +LR osteopenia 18
    • +LR ecchymoses 4
    • All 3 have a specificity of 95%
  • Prevalence of Cushing in obese/metabolic type patients 0.2%
    • 24,000 cases of Cushing/12 million patients with metabolic syndrome = 0.2%
  • 24 hour urinary free cortisol
    • 2-forms: 1) unbound to protein or 2) cortisol unconjugated to sulfuric or hyaluronic acid
    • Unbound cortisol is filtered and reabsorbed. 3% remains in urine.
    • Should measure 24-hour urine creatinine with cortisol to ensure adequate collection
      • Repeat if creatinine is less than 1.5g/day for men and 1g/day in women
    • 24-hour urine cortisol > 62mg/day has +LR 11
  • Dexamethasone Suppression test is used to differentiate ACTH dependent from ACTH independent Cushing syndrome.
    • This is now done by directly measuring ACTH levels
    • Should not be used to diagnose or screen for Cushing syndrome
      • Obese patients with depression will fail to suppress cortisol in response to dexamethasone challenge
  • For Cushingoid exam, but low or zero urinary free cortisol and suppressed ACTH levels suggests exogenous steroid and should prompt a review of medications.
  • ACTH-dependent Cushing syndrome can be due to pituitary secretion from an adenoma or ectopic secretion from a malignant source – typically in the chest.
  • Some experts recommend always doing petrosal sinus sampling due to the high prevalence of non-functioning pituitary adenomas and mortality associated with surgery. Some series report the prevalence of asymptomatic pituitary adenomas as high as 15-40%. Mortality associated with transsphenoidal micro-adenectomy is 1%.
  • ACTH-independent Cushing syndrome is usually caused by an adrenal neoplasm.
    • Characteristics of benign tumors: small (<5cm), <10 Hounsfield units, and have > 60% contrast washout at 15 minutes.
      • Benign tumors can be treated laparoscopically, while malignant tumors typically are resected with an open technique.
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Maester’s Collection: Stable Coronary Artery Disease

Overview

Managing stable ischemic heart disease is challenging in our current age of readily available PCI and improving stent technology.  To paraphrase Shakespeare,

billy-madison-hamlet-scene

“To cath or not to cath, that is the question”

First, we should define the severity of cardiac symptoms, so that everyone is on the same page. A common method used in guidelines and studies is the Canadian Cardiovascular Society Angina Severity Class.

Class I: Ordinary activity such as walking and climbing stairs does not cause angina.
Class II: Slight/modest limitation of ordinary activity such as brisk walking or walking greater than 2 blocks or climbing more than a flight of stairs.
Class III: Marked limitation of ordinary activity such was walking 1-2 blocks or climbing a set of stairs at normal pace.
Class IV: Any physical activity causes discomfort and symptoms maybe present at rest.

Epidemiology

Incidence

Incidence of coronary artery disease is around 1% annually, but increases to nearly 4% in the elderly.

Prevalence

In women, the prevalence of CAD is 5-7% in 45-64 year olds and 10-12% in 65-84 year olds. The prevalence is surprisingly a bit lower in men age 45-64 years at 4-7% compared to women of the same age group. However, the prevalence rises to 12-14% in 65-84 year old men.

Studies

COURAGE
PCI versus OMT for Stable CAD

COURAGE is a North American multi-center RCT. It was composed of 2 parallel groups. The intervention arm was optimal medical therapy (OMT) plus PCI, while the control arm was OMT alone. The study enrolled 2297 patients from 1999 to 2004. Patients were followed for a mean of 4.6 years. Inclusion criteria included Stable CAD, CCS class I, II, III, or stabilized IV, at least one vessel with 70% stenosis, and objective myocardial ischemia. Patients were excluded if they had unstable CCS class IV, marked ischemia during Bruce I – early part of the exercise protocol, LVEF <30%, refractory HF, shock, >50% occlusion of the left main, had revascularization in past 6 months, and if they were deemed unsuitable for PCI. As an aside, I’m uncertain as to what “unsuitable for PCI” means exactly and how much freedom the investigators had to include/exclude based on this criteria, however we must acknowledge it may contribute to bias.

Courage-BaselineDemographicsThe primray endpoint was a composite of death from any cause and nonfatal MI. 

Couage-Outcomes

PCI + OMT did not improve the risk of death or MI, but did improve rates of revascularization. Further, rates of angina or “symptoms” were consistently lower in the PCI group. However, medical therapy alone also improved symptoms by 1-year. Interestingly, in sub group analyses women trended towards benefit as it related to the primary outcome, but in the extended follow up this trend was lost.

Critiques/Criticisms: The predominance of white men limits the generalizability of the COURAGE trial. The rate of medical adherence was impressive and likely could not be achieved in a “real clinical setting”. The majority of patients received older bare metal stents because drug-eluting were not approved until the final 6 months of the study.  Furthermore, 14.5% of lesions were treated only with angioplasty without stenting. Lastly, the results were not stratified by ischemic burden, as it would reason that those with greater ischemic burden would preferentially benefit from PCI.

COURAGE Extended Follow Up

The initial data from the COURAGE study demonstrates that PCI improves angina, but does NOT improve survival or risk of MI. The notion that PCI for stable CAD does not prevent MIs makes physiological sense. MIs are due to plaque rupture, which does not correlate with degree of luminal stenosis. A recently published study follows up on the initial COURAGE study. These patients were followed for 15 years and 381 additional deaths occurred during the extended period. There were a total of 284 deaths (25%) in PCI group and 277 (24%) in OMT. So at even 15 years out, PCI did not demonstrate a survival benefit.

FAME-2
FFR-guided PCI versus OMT

FAME-2 was a multi-center international, non-blinded RCT occurring primarily in United States and Europe. This trial looked to address whether using fractional flow reserve (FFR) guidance to target hemodynamically significant stenosis in stable ischemic disease was of benefit. The primary end point was a composite of all-cause mortality, non-fatal MI, and unplanned hospitalization with urgent revascularization. The follow up for this study was much shorter than for COURAGE at a mere 7-months. 881 patients with stable ischemic heart disease were randomized to either OMT + FFR-guided PCI (n=447) or OMT alone (n=441). Patients who had tortuous or calcified arteries non-amenable to FFR were excluded. Optimal medical therapy was defined as the use of aspirin, beta-1 selective beta blocker, ACEI or ARB, statin +/- ezetemibe titrated to LDL <70, and PCI group also received clopidogrel 75mg for at least a year. Patients undergoing PCI received aspirin and clopidogrel load prior to the intervention.

Patients were primarily male and about 1/4th were diabetic. More than half only had single vessel disease, but more than half had at least one significant lesion in the pLAD or mLAD.

At 7-months, 12.7% of patients suffered the primary end point in the OMT alone group, while only 4.3% in the FFR + OMT group had the primary outcome occur. However, this difference was largely driven by the need for urgent revascularization, while there was no difference in the death or MI. In post-hoc analysis, the authors found a decrease in the rate of death and MI the period between 8 days post intervention and the end of the follow up period. Also there was significant cross-over the study where 44% of patients in the OMT group received a stent and 9% received an additional stent in the FFR group.

Conclusions

  • Optimal medical therapy is equivalent to revascularization in regards to mortality and CV events, particularly MI
  • Both medical therapy and revascularization improve angina
  • Revascularization offers better relief of angina then medical therapy
  • Initial revascularization had decreased need for future revascularization
  • FFR guided therapy may improve death and MI after the immediate periprocedural period, i.e. greater than 7 days.

Tools

Shared decision making tools from the Mayo Clinic

References

  1. National Institutes of Health NH, Lung, and Blood Institute. Morbidity & Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: National Heart, Lung, and Blood Institute; 2012
  2. N Engl J Med 2007; 356:1503-1516
  3. N Engl J Med 2015; 373:1937-1946
  4. N Engl J Med 2012; 367:991-1001
  5. Mayo Clinic Shared Decision Making National Resource Center. Link.