Statin usage in low-risk patients

Former Vice President Dick Cheney was released from the hospital on April 3rd, 2012, 10 days after getting a heart transplant. Cheney waited nearly two years for the transplant. During his life he sustained five heart attacks, the first at age 37 and the most recent one in 2010.

In  a January 4th JAMA editorial, the authors describe that patients were not being helped by a variety of well-established procedures including stenting for stable coronary artery disease:

There is more and more evidence of the superiority of medical therapy over stenting, not only with coronary artery disease, but also with stenotic arteries in your brain: The 30-day rate of stroke or death associated with stenting (14.7%) is nearly 2.5 times as high as the 6% rate associated with stenting in high-risk patients with a 70 - 90 % severe intracranial arterial stenosis.

As is well known, although restriction of diet often results in initial weight loss, more than 80 per cent of obese dieters fail to maintain their reduced weight.

A new study from Australia involved 50 overweight or obese patients without diabetes in a 10-week weight-loss program using a very-low-energy diet. Levels of appetite-regulating hormones were measured at baseline, at the end of the program and one year after initial weight loss.

In this study, the authors analyzed the combined results of four different randomized clinical trials, comparing PCI with CABG in the treatment of Left Main CAD.

Comparing MACCE (major adverse cardiac or cerebrovascular events) they found “nonsignificantly different 1-year rates of MACCE” between the two treatment modalities after 12 months (14.5% vs. 11.8%, P value 0.11).

The studies included were:

As we have reported repeatedly in previews of the SYNTAX trial, the rate of CABG surgeries declined by approximately one-third and that of PCI procedures fell by 4% between 2001 and 2008, according to another study published in JAMA in May, 2011.

Each year, more than 2 million Americans have a heart attack or stroke, of whom more than 800,000 of them die; cardiovascular disease is the leading cause of death in the United States and the largest cause of lower life expectancy among blacks.

Left ventricular diastolic dysfunction is highly prevalent, tends to worsen over time, and is associated with advancing age. Worsening diastolic function can be detected even in apparently healthy persons, the conclusion by the authors of a recent article published in JAMA.

Cardiovascular disease (CVD) is ranked as the number one cause of mortality and is a major cause of morbidity world-wide. Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear.

There are many patients with severe aortic stenosis and coexisting conditions who are not candidates for surgical replacement of the aortic valve. For those patients trans-catheter aortic-valve implantation (TAVI) may be an option.

Patients with heart failure caused by blocked coronary arteries, who are treated with bypass surgery  reduce their risk of dying from heart disease, and also the risk of death from any cause or hospitalization from heart disease, compared with medication alone.

A new study, published in the Januari, 2011 issue of the Journal of Thoracic and Cardiovascular Surgery, reviewed 2-year follow-up outcome data of  1468 CABG patients from the SYNTAX trial.

Current national guidelines for CVD risk reduction are primarily focused on strategies to reduce levels of low-density lipoprotein cholesterol (LDL-C), with the most recent focus being on “lower is better” rather than an effort to increase high-density lipoprotein cholesterol (HDL-C). A careful examination of randomized, controlled trials (RCTs) using statins demonstrates that even with intensive statin therapy and intensive LDL-C lowering, many cardiovascular events are not prevented.

Viron phase 2a data, published in leading cardiovascular journal, circulation: cardiovascular interventions. VT-111 results demonstrate statistically significant reduction in two key biomarkers of cardiac damage.

Senate Finance Committee Chairman Max Baucus (D-Mont.) and Ranking Member Chuck Grassley (R-Iowa) today released a Finance Committee report detailing the case of a doctor who reportedly implanted nearly 600 potentially medically unnecessary stents from 2007 through mid-2009 at St. Joseph Medical Center in Towson, Maryland, and his relationship with the manufacturer of the stents, Abbott Labs.  The Senators’ report found that the questionable stent implantations cost the Medicare program $3.8 million during that period.

In an article[1] published on October 9,2010 in Vascular Health and Risk Management, a British journal, the outcome of PCI in small coronary arteries was studied. Small coronary arteries (with a diameter of <3 mm) account for about 40%–50% of all coronary stenoses.

HbA1c is not a sure-fire tool for Diabetes diagnosis.

The latest SYNTAX results extend CABG's superiority over PCI.

NEW YORK (From Reuters Health) - Performing percutaneous coronary interventions (PCI) in non-infarct-related coronary vessels along with primary PCI for ST-segment elevation myocardial infarction (STEMI) appears to jeopardize patient survival, Canadian researchers reported online June 8 in the European Heart Journal.

CABG is associated with better survival than PCI with DES in patients with non Hemodialysis Dependent (HD) Chronic Kidney Disease (CKD) and multivessel CAD, but CABG patients have a greater short-term risk of needing permanent  hemodialysis.

Point-Counter point 1

Best way to revascularize patients with main stem and three-vessel lesions. Patients should be operated!

Point-Counter point 2

Best way to revascularize patients with main stem and three-vessel lesions: Patients should undergo PCI![i]

The major risk factors of inappropriate diet, physical inactivity, high cholestreol (> 250 mg%), high BMI (>26) and hypertension (>155 mmHg) and smoking, explain at least 75% of new cases of Coronary Artery Disease (CAD). In the absence of these risk factors, CAD is a rare cause of death.

George A. Diamond, and Sanjay Kaul, J. Am. Coll. Cardiol. 2007;50;1604-1609

… While the actual numbers are open to debate, the simple fact is that many patients with stable angina (and an additional number of asymptomatic patients) are undergoing PCI without having received sufficient medical therapy.

Although coronary-artery bypass grafting (CABG) has been the standard of care for patients with left-main or three-vessel coronary disease who require revascularization, percutaneous coronary intervention (PCI) with stenting is also an option in such cases. These two interventions were compared in the SYNTAX trial, which was sponsored by the manufacturer of the Taxus drug-eluting stent.

The Impact of Different Treatment Strategies on Cardiac Death and MI Rates in Patients with Type 2 Diabetes and Stable Coronary Disease, N Engl J Med2009; 360:2503- 2515.

The Coronary Intervention for Persistent Occlusion after Myocardial Infarction (Occluded Artery Trial, (OAT) study evaluated treatment of 2166 high-risk, but otherwise stable survivors of a myocardial infarction and persistent total occlusion of the infarct-related coronary artery.

High risk criteria included an ejection fraction of <50% or proximal occlusion (TIMI flow =0-1). Treatment was randomized to either routine PCI or stenting with Optimal Medical Therapy (OMT) (1082 patients), or OMT alone (1084).

“For Profit Research” with investigators receiving consulting fees from the sponsor (not much progress since 2001):

Medical Journal Editors Demand Accountability from Study Authors, Sponsors, AJHP, 11/1/2001: "clinical studies are increasingly conducted with the goal of marketing products ”

Extended-Release Niacin or Ezetimibe and Carotid Intima–Media Thickness (The ARBITER 6–HALTS trial, Taylor et al., NEJM, 11/15/2009): In a recent study, the effect of  extended-release niacin (Niaspan, target dose, 2000 mg per day) was compared with ezetimibe (Zetia, 10 mg per day) in a small group of 208 patients with established Coronary Artery Disease (CAD). All these patients had been on long-term Statin therapy.

Combining Cardiac Surgery and surgery for carotid stenosis is not effective in the prevention of Stroke.

Low Diagnostic Yield of Elective Coronary Angiography (From: Manesh R. Patel, M.D.,et al.,N Engl J Med 362;10, 886-895)

Improved medical therapy equals Percutaneous Coronary Intervention (PCI) for angina relief in patients with stable Coronary Artery Disease.

Although 40-65% of patients admitted for treatment of an acute heart attack with percutaneous coronary intervention (PCI) have multiple blockages, current guidelines strongly suggest to limit the procedure to the blocked artery (the culprit vessel).

PCI in “Non-culprit coronary arteries” is associated with a significantly increased risk of dying, as Armstrong and colleagues of the APEX-AMI trial recently published in the European Heart Journal of June, 2010.

“Primary composite outcomes” (lumping complications together into one composite complication), allows shading of negative results that only become visible with careful study of a publication. In the CREST study described below, the authors combined procedural death, stroke and myocardial infarction together into a composite complication. In doing so they found no outcome difference between Carotid artery stenting (CAS) and Endarterectomy (CEA).

I strongly disagree with the conclusion as well as this kind of data manipulation, and will address the issue in my analysis of this paper:

Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)[1], a new study published in the latest issue of the NEJM, examined treatment outcomes for Carotid Artery Disease, a major cause of stroke. Stroke is the third most common cause of death among adults and the leading cause of long-term disability. CREST compared Carotid Artery Stenting (CAS) with Carotid Artery Stenting (CAS) as treatment of severe Carotid Artery Disease.

CAS was associated with more than double the mortality rate of CEA (Hazard Ratio (HR): 2.25) and an almost triple rate of ipsilateral stroke (HR: 2.67). The incidence of Myocardial Infarction (MI) in CSA patients occurred at half the rate of CEA treated patients.

The results did not change substantially during the 4-yr follow-up period:

However, despite this the authors concluded that  “… CREST results indicate that carotid-artery stenting and carotid endarterectomy were associated with similar rates of the primary composite outcome — periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke — among men and women with either symptomatic or asymptomatic carotid stenosis. However, the incidence of periprocedural stroke was lower in the endarterectomy group than in the stenting group, whereas the incidence of periprocedural myocardial infarction was lower in the stenting group, … with younger patients having a slightly better outcome with carotid artery stenting and older patients having a better outcome with carotid endarterectomy…”

The study was supported by Abbott Vascular Solutions (formerly Guidant), including donations of Accunet and Acculink systems (the stents used), equivalent to approximately 15% of the total study costs.

An editorial[2] accompanying this article contradicted the CREST conclusions: … “the results are broadly consistent with those in previous trials. Namely, carotid-artery stenting is associated with a higher periprocedural risk of stroke or death, a difference that was still significant at 4 years. A recent meta-analysis of 11 randomized trials performed through 2009 (not including CREST) showed that carotid endarterectomy was superior to carotid-artery stenting, … We conclude that until more data are available, carotid endarterectomy remains the preferred treatment for most patients with symptomatic carotid stenosis”...

Remarks

I agree for the most part with the editorial but would the additional comments:

Treatment of Carotid disease has as goal the prevention of stroke through restoration of blood flow.

• Major Ipsilateral stroke often translates into a permanent disability such as hemiparesis. Prevention of this complication is the one and only goal of any carotid intervention.
• Peri-operative MI is a rare event, rarely of clinical consequence, and largely preventable in the hands of an experienced surgical and anesthesia team.
• The CREST analysis suggests that Death, Stroke and peri-procedural MI are equal complications, an absurd conclusion.
• Even though the more than double CSA mortality rate did not reach statistical significance in this study, it has in a number of other publications.

The Appendix listed together with the CREST publication shows the following[3]:

Somehow this page did not make it to the article. Why? Is it because the authors thought this to be meaningless information, or is it because the results are contradictory to the wished-for corporate sponsored outcomes?

As a surgeon with lots of “carotids” under my belt, one of my problems was to decide what to do first, CABG or CEA, since most of my patients had CAD as well as Carotid disease. Modern surgical techniques are so good that peri-operative stroke was not an issue: I cannot remember a single stroke in my patients (nor any mortality). As a procedure, it took about 45 minutes (“skin-to-skin”) to do the operation, discharging the patient 12-24 hours later. I doubt a stent placement can be done any quicker, and it certainly costs a lot more than two sutures and the occasional patch (the cost of OR and Lab estimated as equivocal).

So what do you prefer, an expensive stent with more than double the mortality and an almost triple stroke rate, in addition to which patients now need to be managed on a regimen of anti-platelet drugs with all the associated  risks (thrombosis etc.)?

And what about another industry sponsored study only confirming what so many other investigations have found, i.e. that CEA is a superior treatment option for carotid artery disease? Or the authors’ conclusions, contradicting their own results?

DR T

[1] Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis, Thomas G. Brott, M.D.et al, (N Engl J Med 363:11-23)

[2] Carotid-Artery Stenting in Stroke Prevention, Stephen M. Davis, M.D., and Geoffrey A. Donnan, M.D., (N Engl J Med 36: 80-82)

[3] Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis. N Engl J Med 2010;363:11-23 Supplementary Appendix, Brott TG et al. (N Engl J Med 363:11-23)

(From: Low Diagnostic Yield of Elective Coronary Angiography, Manesh R. Patel, M.D.,et al.,N Engl J Med 362;10, 886-895)