HDL Remains Important Risk Predictor Even with Low LDL

June 3, 2007
Wayne Kuznar

Internal Medicine World Report, May 2006, Volume 0, Issue 0

ATLANTA—A new analysis of the Treating to New Targets (TNT) study is a timely reminder to primary care physicians that measuring levels of high-density lipoprotein cholesterol (HDL-C) remains an important predictor of cardiovascular (CV) risk in patients who achieve low-density lipoprotein cholesterol (LDL-C) targets with statin therapy.

This finding adds to previous evidence showing that HDL-C represents an additional therapeutic goal independent of LDL-C levels, said Philip Barter, MD, of the Heart Institute, Sydney, Australia, who presented the data at the 55th annual scientific session of the American College of Cardiology.

The finding from TNT “suggests that HDL-C should be an important consideration even in patients whose LDL-C levels are intensively managed,” he said. Despite clear evidence from previous research that a low HDL-C level is an important risk factor for CV disease, the emphasis in clinical practice has mainly been on lowering LDL-C levels, and much less attention has been paid to the need to raise low levels of HDL-C.

TNT was a randomized, double-blind, multicenter study that included 10,001 adults with clinically evident coronary heart disease. Following an open-label, run-in phase with atorvastatin (Lipitor), 10 mg/day, patients with LDL-C <130 mg/dL were randomized to double-blind treatment with atorvastatin, 10 or 80 mg/day, and followed for a median of 4.9 years.

Major CV events were calculated by quintiles of on-treatment HDL-C (<38, 38 to <43, 43 to <48, 48 to <55, and ≤55 mg/dL). Patients in each quintile were also bifurcated according to on-treatment LDL-C level (≤80 mg/dL or >80 mg/dL).

There was an inverse relationship between the incidence of major CV events and HDL-C quintile. Incidences ranged from approximately 12% in the 2 lowest HDL-C quintiles to <8% in the highest quintile.

&#8220;Based on these data, a 1-mg/dL increment in HDL-C concentration in the TNT study was associated with an approximate 2% decrement in the relative risk of a major cardiovascular event,&#8221; said Dr Barter. &#8220;To put this result into context, a 1-mg/dL reduction in LDL-C during this study resulted in a reduction of 0.7% in the incidence of major cardiovascular events.&#8221;

The relationship between on-treatment HDL-C levels and the frequency of major CV events was maintained in both atorvastatin treatment groups. It was also maintained in the ≤80-mg/dL and >80-mg/dL LDL-C subgroups.

&#8220;Having low HDL cholesterol is a risk whether LDL cholesterol is above or below 80 mg/dL,&#8221; said Dr Barter. &#8220;From what we know epidemiologically, we suspect that if you raise HDL-C artificially, it will reduce the event rate.

&#8220;Even with the most intensive statin therapy, a residual risk for cardiovascular disease is apparent,&#8221; he said. &#8220;Reductions in the residual risk apparent with statin therapy may be achieved by complementing statins with treatments that target other components of the dyslipidemic state.&#8221;


This new analysis is a useful reminder to physicians of the role of the &#8220;other&#8221; lipids in CV disease.

Patients who achieve LDL-C reductions with statin therapy remain at risk for CV disease if their HDL-C levels are low.

Low HDL-C levels (≤50 mg/dL in women, ≤40 mg/dL in men) are a risk factor, regardless of the patient&#8217;s LDL-C levels.

Other data from a registry of 155 hospitals in Germany show that HDL-C levels influence in-hospital and 1-year outcomes, based on data from 10,690 patients admitted with acute coronary syndromes (ST-segment elevation and non&#8211;ST-segment elevation myocardial infarction over 2.5 years.

Led by Frank Towae, MD, of the MI Research Institute, Ludwigshafen, Germany, investigators compared patients with high HDL-C (>50 mg/dL for women and >40 mg/dL for men) with those with low HDL-C (≤50 mg/dL for women and ≤40 mg/dL for men) on admission.



In-hospital mortality was 6.1% in the low HDL-C group and 4.7% in the high HDL-C group ( <.01). At 1 year, mortality was again significantly higher in the patients with low versus high HDL-C levels at admission (9.9% vs 6.9%; <.01).

&#8220;Independent of the level of LDL cholesterol, high HDL cholesterol levels were associated with a 19% decreased hospital mortality and with a 25% decreased 1-year mortality,&#8221; said Dr Towae.

PFO Closure Eases, but Doesn&#8217;t Eliminate, Migraine

By Wayne Kuznar

Atlanta&#8212;Closing a large patent foramen ovale (PFO) in patients with migraine headaches does reduce the frequency and severity of such headaches but is no better than preventive medication at completely eliminating migraines, reported investigators at the 55th annual session of the American College of Cardiology.

Right-to-left shunting of blood through a PFO is thought to trigger migraine in susceptible people by allowing substances in the venous blood to bypass the lung filter, said Peter Wilmshurst, MD, of the Royal Shrewsbury Hospital, Shrewsbury, United Kingdom. Several previous observational studies have found that 70% to 90% of patients had their migraines improved or cured, with follow-up as long as 30 months, with PFO closure that was done for other medical reasons.

These observations prompted Dr Wilmshurst and colleagues to design the first prospective, randomized, double-blind, sham-controlled study to assess PFO closure for relieving migraine. The study included 147 patients from 13 centers in the United Kingdom. The patients had severe, frequent migraines with aura and a medium-to-large PFO and were randomized to PFO closure or sham intervention.

Patients had to be refractory to 2 preventive medications from 2 different drug classes and suffer ≤5 migraines in a month to be eligible.

PFO closure was accomplished by threading a catheter through a femoral vein in the groin and into the right side of the heart. The catheter- mounted with a pair of spring-loaded, umbrellalike patches-is then passed into the left atrium through the PFO. After the first umbrella is opened, the catheter is pulled back into the right atrium and the second umbrella is opened, forcing the 2 patches together to form a tight seal.

The patients continued taking any migraine medications they had been using, with follow-up at monthly intervals over 6 months by a headache specialist who was unaware of the group to which the patients had been assigned.

The study did confirm the large shunt rate in PFO patients with migraine, said Dr Wilmshurst. Of the 432 patients screened for the study with contrast transthoracic echocardiography, 260 (60.2%) had an atrial right-to-left shunt. A large atrial shunt was found in 37.7% of the patients. &#8220;The large shunt rate is 6 times that in the general population,&#8221; he said.

The primary end point-complete elimination of headaches-was achieved by 3 patients in each group. However, &#8220;using more conventional migraine trial end points, significant differences were found,&#8221; said Andrew Dowson, MD, of the King&#8217;s Headache Services at King&#8217;s College Hospital, London, principal headache specialist involved in the study.


Specifically, 42% of those undergoing PFO closure had a ≤50% reduction in headache days compared with just 23% of those undergoing the sham procedure ( = .038).

Furthermore, headache burden, a measure of the frequency times the duration of headaches, was reduced significantly in the treatment group (P = .033), but this was not the case in the sham-procedure group. &#8220;The treatment effect seen in frequency and duration appears to improve over time,&#8221; said Dr Dowson.

With PFO closure, &#8220;we&#8217;re opening up an intriguing new option for some patients,&#8221; he said. PFO closure may be an alternative to taking chronic medications over the long-term.

Dr Dowson added, &#8220;The MIST [Migraine Intervention with STARFlex Technology] data may indicate which patients are most likely to show a significant response.&#8221;