journalClub

Today’s NEJM has two articles on statin therapy and achieved LDL and CRP levels in relation to coronary disease.

The first article, from Harvard, is a substudy of the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 study (I challenge you to reread the name of this study once and then repeat it from memory). This trial was a 2×2 study of 80 mg vs. 40 mg of atorvastatin and of the antibiotic gatifloxacin vs. placebo, looking at event rates in 3745 patients who had had acute coronary syndromes. In this substudy, LDL levels and CRP levels were evaluated at 30 days after randomization.

Statin therapy reduced LDL levels significantly; CRP levels were also reduced. There was very little correlation between LDL levels achieved and CRP levels achieved. Cardiac event rates correlated independently with both LDL and CRP. In other words, lower CRP levels correlated with lower event rates, independently of achieved cholesterol reduction.

The second study, from the Cleveland Clinic, was also a substudy of another trial, Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL), which examined atherosclerosis progression using intracoronary ultrasound in patients randomized to 80 mg of atorvastatin vs. 40 mg of pravastatin. Ultrasound was performed and lipids and CRP were obtained at baseline and after 18 months.

The results of this trial were similar to the first: there was little correlation between CRP and lipid levels. Atherosclerosis progression was independently correlated with both LDL and CRP changes between baseline and follow-up.

Comment

Now that the homocysteine fad has waned a bit, commercial laboratories are aggressively promoting profitable high sensitivity CRP measurement. It certainly is an interesting concept, since atherosclerosis is not the gradual, pipe-clogging process that it used to be viewed as, but rather a much more dynamic and inflammatory one. Inflammation and CRP are related, and CRP has prognostic value in vascular disease. It may well turn out that targetting CRP levels when deciding on and dosing statin therapy will be just as important as following LDL levels. Perhaps CRP will allow us to forgo statin therapy in some patients and force us to be more aggressive in others.

However, just because statin-treated patients with lower CRP reductions do better than those with lesser reductions does not automatically prove that targetting statin doses to CRP levels will guarantee the same results. What is needed is a clinical trial that demonstrates that patients whose therapy is guided by CRP do as well as patients whose therapy is fixed and high-dose, for example.

Having said that, the increasingly convincing inflammatory theory of atherosclerosis does make measurement and use of the CRP attractive. One more piece of the puzzle.

Patients undergoing vascular surgery are at higher risk for cardiovascular events. Despite published guidelines, the exact approach to pre-operative cardiac evaluation for these patients varies significantly. The report of a VA cooperative study in last week’s NEJM looked at the value of prophylactic coronary-artery revascularization before elective major vascular surgery.

Patients undergoing elective AAA repair or surgery for PVD of the legs were referred for cardiac catheterization if they were felt to be at increased risk for cardiac complications. The exact reasons for referral were variable and included abnormal thallium stress test and high risk based on clinical criteria. Patients were then eligible for randomisation if they had significant coronary disease of at least one vessel and did not have left main disease, aortic stenosis or an EF less than 20%.

510 patients were randomized to either prophylactic revascularization (CABG or angioplasty, at the discretion of the cardiologists) or no revascularization. In the revascularization group, 99 underwent CABG, 141 angioplasty. After mean follow-up of 2.7 years there was no difference in mortality in the two groups (about 22%).

This is the first study to randomize patients to yes-or-no cardiac revascularization prior to vascular surgery. Given the improvement in medical therapy and the peri-operative use of beta-blockers (84% of patients received them in this study), the result is not surprising but is important.

There are some caveats: patients with left main disease were excluded from randomization. Thus, one cannot use these results to say that there is never a need for pre-operative coronary angiography. Furthermore, no-revascularization prior to vascular surgery is not “never” — 8% of patients randomized to this approach underwent coronary revascularization after their elective surgery.

In my post about the recent NEJM article on ablation for atrial fibrillation, I commented that “… it is not clear to me how exactly to evaluate a comparison of an ejection fraction in atrial fibrillation (the baseline) with one obtained in normal sinus rhythm…”

The corresponding author of this article, Dr. Pierre Jais, has emailed me this reply:

I would like to thank you for your comments and interesting web site.

I just would like to emphasize that the baseline echographic EF was acquired just after the ablation procedure, in sinus rhythm, to overcome the
limititation you pointed out.

Best regards.

Pierre Jais

I went back to the article, to see if I had misunderstood or misstated the methods. The description of the echocardiographic determination of ejection fraction at baseline is as follows:

Patients were routinely admitted two days before the ablation procedure for baseline evaluation. Treatment with oral anticoagulants, taken by all the patients, was stopped on admission, and treatment with all antiarrhythmic drugs, except amiodarone, was stopped for an appropriate period before ablation. Heart rate and rhythm were monitored with the use of 48-hour ambulatory electrocardiography. Transesophageal echocardiography was performed to rule out atrial thrombi, and transthoracic echocardiography was performed to evaluate cardiac structure and function. Echocardiographic measurement of the left ventricular ejection fraction was standardized with the use of Simpson’s biplane method for all patients during the initial hospitalization and subsequent visits.

From the above description, I don’t think it was unreasonable to assume that the initial EF was determined while the patients were still in atrial fibrillation.

Thus, the author’s reply represents a significant clarification.