Saturday, November 22, 2008

AHA 2008 roundup

I’m late with this and it’s all been posted elsewhere, so why here and now?

Very seldom do medical research findings warrant coverage as breaking news. Rare findings which are really earth shattering are often not appreciated as such until months or years later. Many media reports from the AHA sessions were little more than sound bites and many were over hyped. When those reports came out I was too busy and tired to blog. Now, after an opportunity to check primary sources and think about the findings, I offer my own take on some of the ones that interested me.

JUPITER The NEJM abstract concludes with:

In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events.

So---statin treatment works for primary prevention in patients with “normal” cholesterol levels. Earthshaking? Hardly. We knew this a decade ago. Remember AFCAPS/TexCAPS?

This study helps confirm the findings of AFCAPS/TexCAPS and (I think) extends them to even healthier patients. The study was hyped and probably won’t (or shouldn’t) change practice much. For a thoughtful and nuanced view of JUPITER see the accompanying NEJM editorial.

When considering the use of statins for primary prevention in low risk patients one must weigh in absolute risk reduction (the NNT in JUPITER was 120 patients treated for 1.9 years), cost effectiveness (Dr. Wes does the math for Crestor here) and the risks of years and years of statin use.

What’s the significance of the hs-CRP test? Although statins (at least some) lower CRP levels, the main significance is that CRP, like diabetes, smoking and hypertension, is a risk factor and the higher the patient’s risk the bigger the bang for the buck with LDL reduction. This was shown several years ago for hs-CRP in a subgroup analysis of AFCAPS/TexCAPS. The statin used in that study, lovastatin (Mevacor) is now on Walmart’s $4 generic list. Do the math again and it looks a good deal better from a cost effectiveness standpoint.

Negative Thinking Predicts Depression in Heart-Failure Patients. Did we really need a study to figure that out?

LDL particle concentration versus LDL cholesterol concentration Via Reuters Health:

Risk of cardiovascular disease can remain high even after low-density lipoprotein (LDL) cholesterol target levels have been reached in patients with the metabolic syndrome.

We’ve known this for years. Although the guidelines have not emphasized it enough the concept of residual risk after statin therapy (RRAST) is emerging. LDL reduction is important and, in the aggregate, the lower the better. In many individual patients, though, it’s not enough. The fact that statin trials show RRR’s of 25-30% begs the question “why not 80%, why not 100%?” (Bob Superko addressed this in his classic paper here, and, along with Spencer King, provided an update here).

From the Reuters piece:

Risk may be better gauged with low-density lipoprotein particle concentration, investigators announced here at the American Heart Association's Scientific Sessions 2008.

High LDL particle concentration relative to LDLC concentration reflects the atherogenic lipoprotein profile (ALP) characterized by abnormally small LDL particle diameter. This is a phenotypic expression of the metabolic syndrome and for practical purposes many regard it as synonymous (this is not invariably so---the ALP is nicely explained in the Superko papers linked above). The ALP and the associated metabolic syndrome represent the most common genetic causes of CAD and are certainly the most important contributors to RRAST.

Perhaps most concerning from the AHA presentation was this:

"Lipoprotein particle concentration may go up as LDL cholesterol levels are lowered with treatment," Dr. Robert Rosenson of the University of Michigan at Ann Arbor told Reuters Health after he presented his team's findings regarding 401 patients with metabolic syndrome and a 10-year risk of coronary heart disease greater than10%.

This is a finding that needs better understanding. Do statins somehow turn on genes that cause metabolic syndrome? What’s the solution? When the patient is at goal with statin therapy the RRAST must be assessed. The determination of triglycerides, HDLC and the total/HDL ratio are helpful. If the metabolic syndrome is evident diet and exercise are the best treatments, and drug therapy options include niacins and fibrates.

It has been suggested that lowering LDLC to extremely low concentrations with statins may offset this residual---lower the cholesterol concentration enough with statins and eventually the particle concentration will go down, perhaps. In that connection note a little mentioned aspect of JUPITER---LDLC was lowered to a median of 55 and RRR’s were on the order of an unprecedented 50% in contrast to the 25-30% reductions cited for other statin trials. Maybe there’s something to it.

Vitamins C and E Here we go again. No benefit. Vitamin E may even be harmful. There’s never been any favorable evidence for vitamin C and vitamin E was blown out of the water years ago. That hasn’t stopped some from promoting it, though.

Irbesartan and heart failure with preserved EF

During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes.

Again, this result for irbesartan (Avapro) is not new regarding ARB’s and heart failure with preserved ejection fraction (HFPEF). The CHARM-preserved study reached a similar conclusion years ago with candesartan (Atacand). There is little in the way of evidence from clinical trials to guide clinicians in the long term treatment of HFPEF. The best we can do now is to do a better job of treating their co-morbidities, of which they have many. If those co-morbidities include hypertension irbesartan as well as other antihypertensive agents might be reasonable choices. To say that irbesartan is of no value in the treatment of patients with HFPEF is simplistic. (Patients to be included in the irbesartan study could not have uncontrolled hypertension).

Perioperative beta blockers---another negative meta-analysis. From the Lancet paper:

The ACC/AHA guidelines committee should soften their advocacy for this intervention until conclusive evidence is available.

Well, they already have, quite some time ago. Now, the only strong guideline recommendation, for practical purposes, is that if the patient is already on a beta blocker for cardiovascular indications it should be continued perioperatively.

Statin dose-response relationships: Search Me This one’s a little complicated. Simvastatin (Zocor) was only marginally better at 80 mg in comparison to 20 mg daily in terms of reducing events in a secondary prevention study. But when this study is taken into account with multiple other statin trials the notion that lower LDLC is better still holds. Most disturbing was the markedly increased incidence of myopathy at the 80 mg dose. According to expert commentary about this study, if it’s desirable to seek very low LDLC targets in your patient it may be better to switch to a safer statin as opposed to increasing simvastatin to 80 mg. Simvastatin is safe when used according to the product safety labeling. This labeling, however, particularly the section on drug interactions, has become so complicated that simvastatin is getting a little tricky to prescribe. One has to review the patient’s entire med list and, unless one has a photographic memory, look up the labeling each time.

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