Bruce Jancin

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – In terms of preserving exercise capacity and lowering elevated N-terminal pro-B-type natriuretic peptide levels, calcium channel blockers outperformed beta-blockers for rate control in patients with permanent atrial fibrillation.

The findings were noted in the RATAF (Norwegian Rate Control in Atrial Fibrillation) trial, a randomized, crossover, investigator-blinded study. RATAF also showed that diltiazem and verapamil significantly reduced arrhythmia-related symptoms, while carvedilol and metoprolol did not. Moreover, mean 24-hour ventricular heart rate was significantly lower during calcium channel blocker therapy than when subjects were on beta-blockers, according to Dr. Sarah Reinvik Ulimoen, of Baerum Hospital in Rud, Norway.

"Treatment with calcium channel blockers for rate control in atrial fibrillation should be considered more often in patients not needing a beta-blocker – that is, in patients without systolic heart failure or coronary heart disease," she said at the annual scientific sessions of the American Heart Association.

She reported on 60 RATAF participants with permanent AF, a normal left ventricular ejection fraction, and no coronary heart disease. The subjects received for 3 weeks each and in random sequence, once-daily diltiazem at 360 mg, verapamil at 240 mg, metoprolol at 100 mg, and carvedilol at 25 mg. At baseline and on the final day of each 3-week-long treatment period, the patients performed a bicycle ergometer maximal cardiopulmonary exercise test with measurement of peak oxygen uptake.

Blood samples for measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were taken at rest, peak exercise, and recovery. NT-proBNP is a biomarker widely utilized in the diagnosis and monitoring of heart failure. In addition, NT-proBNP is known to be elevated in patients with AF, even if they have normal systolic function.

The two calcium channel blockers preserved patients’ exercise capacity: Mean VO_2max on the bike was 23.1 mL/kg per minute at baseline, 23.7 mL/kg per minute while subjects were on diltiazem, and 23.1 mL/kg per minute when they were on verapamil.

In contrast, mean VO_2max was significantly reduced relative to baseline when patients were on beta-blocker therapy: 21.1 mL/kg per minute with metoprolol and 20.0 mL/kg per minute with carvedilol.

Mean NT-proBNP levels at rest were 1,039 pg/mL at baseline and significantly lower during calcium channel blocker therapy: 831 pg/mL while patients were on diltiazem and 897 pg/mL on verapamil. When patients were on a beta-blocker, however, their resting NT-proBNP was significantly greater than at baseline: 1,332 pg/mL for metoprolol and 1,205 pg/mL for carvedilol.

The same relationships seen when NT-proBNP was measured at rest held true when the biomarker was measured at peak exercise or during recovery: Mean levels were significantly reduced compared with baseline if patients were on calcium channel blockers for rate control, and significantly elevated above baseline while they were on beta-blockers. An inverse relationship was evident between exercise capacity and NT-proBNP: As maximum oxygen uptake went down, NT-proBNP levels went up.

Dr. Ulimoen noted that the exact mechanism underlying the increased levels of NT-proBNP in AF is unknown. Possibilities include myocardial stretching, oxidative stress in the atrial wall, and local ischemia. It’s believed that the major source of the NT-proBNP present in AF is the atria, not the ventricles as in heart failure.

As to why beta-blocker therapy was associated with higher levels of the cardiac biomarker, Dr. Ulimoen speculated that perhaps the drugs interfere with relaxation of the heart and thus diastolic filling; it is thought that NT-proBNP levels may reflect left ventricular filling pressure.

The findings she presented at the meeting regarding peak exercise capacity and changes in NT-proBNP were secondary end points in RATAF. The primary outcomes – the four rate control drugs’ effects on arrhythmia-related symptoms and mean 24-hour heart rate – were recently published (Am. J. Cardiol. 2012 [doi: 10.1016/j.amjcard.2012.09.020]).

Dr. Ulimoen reported having no financial conflicts.

LOS ANGELES – In terms of preserving exercise capacity and lowering elevated N-terminal pro-B-type natriuretic peptide levels, calcium channel blockers outperformed beta-blockers for rate control in patients with permanent atrial fibrillation.

The findings were noted in the RATAF (Norwegian Rate Control in Atrial Fibrillation) trial, a randomized, crossover, investigator-blinded study. RATAF also showed that diltiazem and verapamil significantly reduced arrhythmia-related symptoms, while carvedilol and metoprolol did not. Moreover, mean 24-hour ventricular heart rate was significantly lower during calcium channel blocker therapy than when subjects were on beta-blockers, according to Dr. Sarah Reinvik Ulimoen, of Baerum Hospital in Rud, Norway.

"Treatment with calcium channel blockers for rate control in atrial fibrillation should be considered more often in patients not needing a beta-blocker – that is, in patients without systolic heart failure or coronary heart disease," she said at the annual scientific sessions of the American Heart Association.

She reported on 60 RATAF participants with permanent AF, a normal left ventricular ejection fraction, and no coronary heart disease. The subjects received for 3 weeks each and in random sequence, once-daily diltiazem at 360 mg, verapamil at 240 mg, metoprolol at 100 mg, and carvedilol at 25 mg. At baseline and on the final day of each 3-week-long treatment period, the patients performed a bicycle ergometer maximal cardiopulmonary exercise test with measurement of peak oxygen uptake.

Blood samples for measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were taken at rest, peak exercise, and recovery. NT-proBNP is a biomarker widely utilized in the diagnosis and monitoring of heart failure. In addition, NT-proBNP is known to be elevated in patients with AF, even if they have normal systolic function.

The two calcium channel blockers preserved patients’ exercise capacity: Mean VO_2max on the bike was 23.1 mL/kg per minute at baseline, 23.7 mL/kg per minute while subjects were on diltiazem, and 23.1 mL/kg per minute when they were on verapamil.

In contrast, mean VO_2max was significantly reduced relative to baseline when patients were on beta-blocker therapy: 21.1 mL/kg per minute with metoprolol and 20.0 mL/kg per minute with carvedilol.

Mean NT-proBNP levels at rest were 1,039 pg/mL at baseline and significantly lower during calcium channel blocker therapy: 831 pg/mL while patients were on diltiazem and 897 pg/mL on verapamil. When patients were on a beta-blocker, however, their resting NT-proBNP was significantly greater than at baseline: 1,332 pg/mL for metoprolol and 1,205 pg/mL for carvedilol.

The same relationships seen when NT-proBNP was measured at rest held true when the biomarker was measured at peak exercise or during recovery: Mean levels were significantly reduced compared with baseline if patients were on calcium channel blockers for rate control, and significantly elevated above baseline while they were on beta-blockers. An inverse relationship was evident between exercise capacity and NT-proBNP: As maximum oxygen uptake went down, NT-proBNP levels went up.

Dr. Ulimoen noted that the exact mechanism underlying the increased levels of NT-proBNP in AF is unknown. Possibilities include myocardial stretching, oxidative stress in the atrial wall, and local ischemia. It’s believed that the major source of the NT-proBNP present in AF is the atria, not the ventricles as in heart failure.

As to why beta-blocker therapy was associated with higher levels of the cardiac biomarker, Dr. Ulimoen speculated that perhaps the drugs interfere with relaxation of the heart and thus diastolic filling; it is thought that NT-proBNP levels may reflect left ventricular filling pressure.

The findings she presented at the meeting regarding peak exercise capacity and changes in NT-proBNP were secondary end points in RATAF. The primary outcomes – the four rate control drugs’ effects on arrhythmia-related symptoms and mean 24-hour heart rate – were recently published (Am. J. Cardiol. 2012 [doi: 10.1016/j.amjcard.2012.09.020]).

Dr. Ulimoen reported having no financial conflicts.

LOS ANGELES – In terms of preserving exercise capacity and lowering elevated N-terminal pro-B-type natriuretic peptide levels, calcium channel blockers outperformed beta-blockers for rate control in patients with permanent atrial fibrillation.

The findings were noted in the RATAF (Norwegian Rate Control in Atrial Fibrillation) trial, a randomized, crossover, investigator-blinded study. RATAF also showed that diltiazem and verapamil significantly reduced arrhythmia-related symptoms, while carvedilol and metoprolol did not. Moreover, mean 24-hour ventricular heart rate was significantly lower during calcium channel blocker therapy than when subjects were on beta-blockers, according to Dr. Sarah Reinvik Ulimoen, of Baerum Hospital in Rud, Norway.

"Treatment with calcium channel blockers for rate control in atrial fibrillation should be considered more often in patients not needing a beta-blocker – that is, in patients without systolic heart failure or coronary heart disease," she said at the annual scientific sessions of the American Heart Association.

She reported on 60 RATAF participants with permanent AF, a normal left ventricular ejection fraction, and no coronary heart disease. The subjects received for 3 weeks each and in random sequence, once-daily diltiazem at 360 mg, verapamil at 240 mg, metoprolol at 100 mg, and carvedilol at 25 mg. At baseline and on the final day of each 3-week-long treatment period, the patients performed a bicycle ergometer maximal cardiopulmonary exercise test with measurement of peak oxygen uptake.

Blood samples for measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were taken at rest, peak exercise, and recovery. NT-proBNP is a biomarker widely utilized in the diagnosis and monitoring of heart failure. In addition, NT-proBNP is known to be elevated in patients with AF, even if they have normal systolic function.

The two calcium channel blockers preserved patients’ exercise capacity: Mean VO_2max on the bike was 23.1 mL/kg per minute at baseline, 23.7 mL/kg per minute while subjects were on diltiazem, and 23.1 mL/kg per minute when they were on verapamil.

In contrast, mean VO_2max was significantly reduced relative to baseline when patients were on beta-blocker therapy: 21.1 mL/kg per minute with metoprolol and 20.0 mL/kg per minute with carvedilol.

Mean NT-proBNP levels at rest were 1,039 pg/mL at baseline and significantly lower during calcium channel blocker therapy: 831 pg/mL while patients were on diltiazem and 897 pg/mL on verapamil. When patients were on a beta-blocker, however, their resting NT-proBNP was significantly greater than at baseline: 1,332 pg/mL for metoprolol and 1,205 pg/mL for carvedilol.

The same relationships seen when NT-proBNP was measured at rest held true when the biomarker was measured at peak exercise or during recovery: Mean levels were significantly reduced compared with baseline if patients were on calcium channel blockers for rate control, and significantly elevated above baseline while they were on beta-blockers. An inverse relationship was evident between exercise capacity and NT-proBNP: As maximum oxygen uptake went down, NT-proBNP levels went up.

Dr. Ulimoen noted that the exact mechanism underlying the increased levels of NT-proBNP in AF is unknown. Possibilities include myocardial stretching, oxidative stress in the atrial wall, and local ischemia. It’s believed that the major source of the NT-proBNP present in AF is the atria, not the ventricles as in heart failure.

As to why beta-blocker therapy was associated with higher levels of the cardiac biomarker, Dr. Ulimoen speculated that perhaps the drugs interfere with relaxation of the heart and thus diastolic filling; it is thought that NT-proBNP levels may reflect left ventricular filling pressure.

The findings she presented at the meeting regarding peak exercise capacity and changes in NT-proBNP were secondary end points in RATAF. The primary outcomes – the four rate control drugs’ effects on arrhythmia-related symptoms and mean 24-hour heart rate – were recently published (Am. J. Cardiol. 2012 [doi: 10.1016/j.amjcard.2012.09.020]).

Dr. Ulimoen reported having no financial conflicts.

LOS ANGELES – Pregnancy loss is strongly associated with increased risks of three different clinical forms of atherosclerotic disease over the subsequent 15 years, a study of more than 1 million Danish pregnant women has shown.

"This is the largest-ever study on the occurrence of atherosclerotic disease after pregnancy loss. This study, taken together with previous studies, implies a possible common underlying pathology linking pregnancy losses and atherosclerosis," said Dr. Mattis F. Ranthe of the Statens Serum Institute, Copenhagen.

The study used Denmark’s comprehensive national cradle-to-the-grave health care registry to track all 1,031,279 Danes who were free of a history of cardiovascular disease at the time they became pregnant during 1977-1988. A total of 8,191 women had one or more stillbirths. There were 151,808 women with one miscarriage, 28,398 with two miscarriages, 5,979 with three, and 2,406 women with four or more miscarriages.

The three expressions of atherosclerosis under study were acute MI, cerebral infarction, and renovascular hypertension. During more than 15 million person-years of follow-up through the registry, there were 2,798 cases of MI, 4,053 cerebral infarcts, and 1,269 diagnoses of renovascular hypertension, Dr. Ranthe reported at the annual scientific sessions of the American Heart Association.

A history of even a single stillbirth was associated with a 2.69-fold increased incidence rate ratio for subsequent MI, a 1.74-fold increase in cerebral infarction, and a 2.42-fold increase in renovascular hypertension after adjustment for age, number of live births, and calendar year.

A robust dose-response relationship was evident between the number of miscarriages and atherosclerotic disease risk. Women with a history of a single miscarriage had an adjusted 1.11-fold increased risk of MI, a 1.13-fold increase in cerebral infarction, and a 1.15-fold greater risk of developing renovascular hypertension during follow-up than did women with no miscarriages. These 11%-15% increases in relative risk were all strongly significant, given the large numbers.

With two miscarriages, the risks of MI, cerebral infarct, and renovascular hypertension were increased 1.18-fold, 1.22-fold, and 1.12-fold, respectively. With a history of three miscarriages, the risks were 0.85, 1.43, and 1.78. And with 4 or more miscarriages, the incidence rate ratio for MI was increased 2.08-fold, that for cerebral infarct was 1.89-fold, and for renovascular hypertension it was 3.78-fold greater than in women with no miscarriages.

Further adjustment for diabetes, smoking, thrombophilia, and polycystic ovarian syndrome left these estimates unchanged.

The risk of each of the three forms of atherosclerosis climbed by 10%-20% with each additional miscarriage. However, the risk wasn’t evenly spread across all age groups. Rather, the risk of developing atherosclerotic disease within the next 15 years was greatest in the youngest women who miscarried. The risk associated with miscarriage late in the period of childbearing potential was far less, the physician noted.

That observation raised a red flag for one audience member.

"If you have younger women of childbearing years having myocardial infarctions earlier on, one tends to think that mechanistically it may be atherosclerosis, but it may actually be due to other issues involving connective tissue diseases. I’d be cautious in using atherosclerosis as a broad pathophysiologic explanation," she said.

Dr. Ranthe agreed.

He reported having no financial conflicts related to this study, which was funded by the Danish Heart Foundation.

LOS ANGELES – Pregnancy loss is strongly associated with increased risks of three different clinical forms of atherosclerotic disease over the subsequent 15 years, a study of more than 1 million Danish pregnant women has shown.

"This is the largest-ever study on the occurrence of atherosclerotic disease after pregnancy loss. This study, taken together with previous studies, implies a possible common underlying pathology linking pregnancy losses and atherosclerosis," said Dr. Mattis F. Ranthe of the Statens Serum Institute, Copenhagen.

The study used Denmark’s comprehensive national cradle-to-the-grave health care registry to track all 1,031,279 Danes who were free of a history of cardiovascular disease at the time they became pregnant during 1977-1988. A total of 8,191 women had one or more stillbirths. There were 151,808 women with one miscarriage, 28,398 with two miscarriages, 5,979 with three, and 2,406 women with four or more miscarriages.

The three expressions of atherosclerosis under study were acute MI, cerebral infarction, and renovascular hypertension. During more than 15 million person-years of follow-up through the registry, there were 2,798 cases of MI, 4,053 cerebral infarcts, and 1,269 diagnoses of renovascular hypertension, Dr. Ranthe reported at the annual scientific sessions of the American Heart Association.

A history of even a single stillbirth was associated with a 2.69-fold increased incidence rate ratio for subsequent MI, a 1.74-fold increase in cerebral infarction, and a 2.42-fold increase in renovascular hypertension after adjustment for age, number of live births, and calendar year.

A robust dose-response relationship was evident between the number of miscarriages and atherosclerotic disease risk. Women with a history of a single miscarriage had an adjusted 1.11-fold increased risk of MI, a 1.13-fold increase in cerebral infarction, and a 1.15-fold greater risk of developing renovascular hypertension during follow-up than did women with no miscarriages. These 11%-15% increases in relative risk were all strongly significant, given the large numbers.

With two miscarriages, the risks of MI, cerebral infarct, and renovascular hypertension were increased 1.18-fold, 1.22-fold, and 1.12-fold, respectively. With a history of three miscarriages, the risks were 0.85, 1.43, and 1.78. And with 4 or more miscarriages, the incidence rate ratio for MI was increased 2.08-fold, that for cerebral infarct was 1.89-fold, and for renovascular hypertension it was 3.78-fold greater than in women with no miscarriages.

Further adjustment for diabetes, smoking, thrombophilia, and polycystic ovarian syndrome left these estimates unchanged.

The risk of each of the three forms of atherosclerosis climbed by 10%-20% with each additional miscarriage. However, the risk wasn’t evenly spread across all age groups. Rather, the risk of developing atherosclerotic disease within the next 15 years was greatest in the youngest women who miscarried. The risk associated with miscarriage late in the period of childbearing potential was far less, the physician noted.

That observation raised a red flag for one audience member.

"If you have younger women of childbearing years having myocardial infarctions earlier on, one tends to think that mechanistically it may be atherosclerosis, but it may actually be due to other issues involving connective tissue diseases. I’d be cautious in using atherosclerosis as a broad pathophysiologic explanation," she said.

Dr. Ranthe agreed.

He reported having no financial conflicts related to this study, which was funded by the Danish Heart Foundation.

LOS ANGELES – Pregnancy loss is strongly associated with increased risks of three different clinical forms of atherosclerotic disease over the subsequent 15 years, a study of more than 1 million Danish pregnant women has shown.

"This is the largest-ever study on the occurrence of atherosclerotic disease after pregnancy loss. This study, taken together with previous studies, implies a possible common underlying pathology linking pregnancy losses and atherosclerosis," said Dr. Mattis F. Ranthe of the Statens Serum Institute, Copenhagen.

The study used Denmark’s comprehensive national cradle-to-the-grave health care registry to track all 1,031,279 Danes who were free of a history of cardiovascular disease at the time they became pregnant during 1977-1988. A total of 8,191 women had one or more stillbirths. There were 151,808 women with one miscarriage, 28,398 with two miscarriages, 5,979 with three, and 2,406 women with four or more miscarriages.

The three expressions of atherosclerosis under study were acute MI, cerebral infarction, and renovascular hypertension. During more than 15 million person-years of follow-up through the registry, there were 2,798 cases of MI, 4,053 cerebral infarcts, and 1,269 diagnoses of renovascular hypertension, Dr. Ranthe reported at the annual scientific sessions of the American Heart Association.

A history of even a single stillbirth was associated with a 2.69-fold increased incidence rate ratio for subsequent MI, a 1.74-fold increase in cerebral infarction, and a 2.42-fold increase in renovascular hypertension after adjustment for age, number of live births, and calendar year.

A robust dose-response relationship was evident between the number of miscarriages and atherosclerotic disease risk. Women with a history of a single miscarriage had an adjusted 1.11-fold increased risk of MI, a 1.13-fold increase in cerebral infarction, and a 1.15-fold greater risk of developing renovascular hypertension during follow-up than did women with no miscarriages. These 11%-15% increases in relative risk were all strongly significant, given the large numbers.

With two miscarriages, the risks of MI, cerebral infarct, and renovascular hypertension were increased 1.18-fold, 1.22-fold, and 1.12-fold, respectively. With a history of three miscarriages, the risks were 0.85, 1.43, and 1.78. And with 4 or more miscarriages, the incidence rate ratio for MI was increased 2.08-fold, that for cerebral infarct was 1.89-fold, and for renovascular hypertension it was 3.78-fold greater than in women with no miscarriages.

Further adjustment for diabetes, smoking, thrombophilia, and polycystic ovarian syndrome left these estimates unchanged.

The risk of each of the three forms of atherosclerosis climbed by 10%-20% with each additional miscarriage. However, the risk wasn’t evenly spread across all age groups. Rather, the risk of developing atherosclerotic disease within the next 15 years was greatest in the youngest women who miscarried. The risk associated with miscarriage late in the period of childbearing potential was far less, the physician noted.

That observation raised a red flag for one audience member.

"If you have younger women of childbearing years having myocardial infarctions earlier on, one tends to think that mechanistically it may be atherosclerosis, but it may actually be due to other issues involving connective tissue diseases. I’d be cautious in using atherosclerosis as a broad pathophysiologic explanation," she said.

Dr. Ranthe agreed.

He reported having no financial conflicts related to this study, which was funded by the Danish Heart Foundation.

PRAGUE  – Optimized pulsed light therapy using Palomar Medical Technologies’ proprietary MaxG handpiece proved safe and efficient for the treatment of port wine stains and capillary malformations in an open study.

The MaxG is next-generation intense pulsed light therapy. The advance lies in a handpiece optimized so as to use a dual-band spectrum with two peaks: one at 500-670 nm and another at 870-1,200 nm. The peak in the visible light range targets small, superficial vessels, while the one in the near infrared addresses deeper vessels. Thus, optimized pulsed light (OPL) is able to achieve uniform heating and pulse width matched to a target vessel’s depth and size, Dr. Maurice A. Adatto explained at the annual congress of the European Academy of Dermatology and Venereology.

For years, pulsed dye laser therapy has been considered the gold standard in the treatment of vascular lesions. But recent published data demonstrate that while the laser can coagulate vessels quite nicely at the surface, the coagulation isn’t nearly as good for deeper vessels. In animal models, the OPL achieves greater increases in temperature compared with the pulsed dye laser at the purpuric threshold fluence in deeper and larger capillaries, said Dr. Adatto, who is medical director of the SkinPulse Dermatology & Laser Center in Geneva.

Dr. Adatto presented a two-center series of 16 OPL-treated adults and adolescents with vascular lesions on the face, neck, trunk, and lower limbs. The procedures were performed by him at the center in Geneva, and by his coinvestigator Dr. David Friedman in Jerusalem. The OPL handpiece was attached to Palomar’s Icon intense pulsed light device.

Outcomes were objectively assessed using the Antera 3D camera, made by Miravex, which provides high-definition clinical photographs along with quantitative measurement of hemoglobin and melanin clearance in treated areas. Assessments were done at 2-4 days and 1-2 months post-treatment.

The efficacy was impressive, and the side effects were far milder and more transitory than can occur with pulsed dye laser therapy, according to the dermatologist.

The majority of patients – 10 of 16 – achieved 50% or greater improvement in one to four OPL sessions. After the first treatment, four patients had roughly a 20% improvement, five were 25%-49% better, three showed 50%-74% clearance, and two patients showed 80% and 100% clearance.

Side effects consisted of 3-5 days of purpura and 1-3 days of local edema. To date, OPL for vascular lesions hasn’t resulted in any scars or in hypo- or hyperpigmentation.

As for the technical details, Dr. Adatto utilized one pass with 50 J/cm² at 10 ms, while Dr. Friedman used a two-pass technique: the first at 34-36 J/cm² at 10 ms, followed by a second at 22-28 J/cm² at 5 ms. Treatment sessions were carried out at 4- to 6-week intervals.

In response to audience questions, Dr. Adatto said that his anecdotal experience has been that once a patient achieves greater than about 50% improvement, be it with a single OPL treatment session or after three, the therapeutic gain of additional sessions is smaller than with the initial ones.

"You can gain another 10% or so with another session for someone who has 70% improvement, but that’s it. You will reach a plateau," he said.

Dr. Adatto is now planning a similar study using OPL to treat vascular lesions in a pediatric population.

The study was funded by Palomar Medical Technologies. Dr. Adatto has received research funds from and is an adviser to Palomar and numerous other laser and intense pulsed light device manufacturers.

PRAGUE  – Optimized pulsed light therapy using Palomar Medical Technologies’ proprietary MaxG handpiece proved safe and efficient for the treatment of port wine stains and capillary malformations in an open study.

The MaxG is next-generation intense pulsed light therapy. The advance lies in a handpiece optimized so as to use a dual-band spectrum with two peaks: one at 500-670 nm and another at 870-1,200 nm. The peak in the visible light range targets small, superficial vessels, while the one in the near infrared addresses deeper vessels. Thus, optimized pulsed light (OPL) is able to achieve uniform heating and pulse width matched to a target vessel’s depth and size, Dr. Maurice A. Adatto explained at the annual congress of the European Academy of Dermatology and Venereology.

For years, pulsed dye laser therapy has been considered the gold standard in the treatment of vascular lesions. But recent published data demonstrate that while the laser can coagulate vessels quite nicely at the surface, the coagulation isn’t nearly as good for deeper vessels. In animal models, the OPL achieves greater increases in temperature compared with the pulsed dye laser at the purpuric threshold fluence in deeper and larger capillaries, said Dr. Adatto, who is medical director of the SkinPulse Dermatology & Laser Center in Geneva.

Dr. Adatto presented a two-center series of 16 OPL-treated adults and adolescents with vascular lesions on the face, neck, trunk, and lower limbs. The procedures were performed by him at the center in Geneva, and by his coinvestigator Dr. David Friedman in Jerusalem. The OPL handpiece was attached to Palomar’s Icon intense pulsed light device.

Outcomes were objectively assessed using the Antera 3D camera, made by Miravex, which provides high-definition clinical photographs along with quantitative measurement of hemoglobin and melanin clearance in treated areas. Assessments were done at 2-4 days and 1-2 months post-treatment.

The efficacy was impressive, and the side effects were far milder and more transitory than can occur with pulsed dye laser therapy, according to the dermatologist.

The majority of patients – 10 of 16 – achieved 50% or greater improvement in one to four OPL sessions. After the first treatment, four patients had roughly a 20% improvement, five were 25%-49% better, three showed 50%-74% clearance, and two patients showed 80% and 100% clearance.

Side effects consisted of 3-5 days of purpura and 1-3 days of local edema. To date, OPL for vascular lesions hasn’t resulted in any scars or in hypo- or hyperpigmentation.

As for the technical details, Dr. Adatto utilized one pass with 50 J/cm² at 10 ms, while Dr. Friedman used a two-pass technique: the first at 34-36 J/cm² at 10 ms, followed by a second at 22-28 J/cm² at 5 ms. Treatment sessions were carried out at 4- to 6-week intervals.

In response to audience questions, Dr. Adatto said that his anecdotal experience has been that once a patient achieves greater than about 50% improvement, be it with a single OPL treatment session or after three, the therapeutic gain of additional sessions is smaller than with the initial ones.

"You can gain another 10% or so with another session for someone who has 70% improvement, but that’s it. You will reach a plateau," he said.

Dr. Adatto is now planning a similar study using OPL to treat vascular lesions in a pediatric population.

The study was funded by Palomar Medical Technologies. Dr. Adatto has received research funds from and is an adviser to Palomar and numerous other laser and intense pulsed light device manufacturers.

PRAGUE  – Optimized pulsed light therapy using Palomar Medical Technologies’ proprietary MaxG handpiece proved safe and efficient for the treatment of port wine stains and capillary malformations in an open study.

The MaxG is next-generation intense pulsed light therapy. The advance lies in a handpiece optimized so as to use a dual-band spectrum with two peaks: one at 500-670 nm and another at 870-1,200 nm. The peak in the visible light range targets small, superficial vessels, while the one in the near infrared addresses deeper vessels. Thus, optimized pulsed light (OPL) is able to achieve uniform heating and pulse width matched to a target vessel’s depth and size, Dr. Maurice A. Adatto explained at the annual congress of the European Academy of Dermatology and Venereology.

For years, pulsed dye laser therapy has been considered the gold standard in the treatment of vascular lesions. But recent published data demonstrate that while the laser can coagulate vessels quite nicely at the surface, the coagulation isn’t nearly as good for deeper vessels. In animal models, the OPL achieves greater increases in temperature compared with the pulsed dye laser at the purpuric threshold fluence in deeper and larger capillaries, said Dr. Adatto, who is medical director of the SkinPulse Dermatology & Laser Center in Geneva.

Dr. Adatto presented a two-center series of 16 OPL-treated adults and adolescents with vascular lesions on the face, neck, trunk, and lower limbs. The procedures were performed by him at the center in Geneva, and by his coinvestigator Dr. David Friedman in Jerusalem. The OPL handpiece was attached to Palomar’s Icon intense pulsed light device.

Outcomes were objectively assessed using the Antera 3D camera, made by Miravex, which provides high-definition clinical photographs along with quantitative measurement of hemoglobin and melanin clearance in treated areas. Assessments were done at 2-4 days and 1-2 months post-treatment.

The efficacy was impressive, and the side effects were far milder and more transitory than can occur with pulsed dye laser therapy, according to the dermatologist.

The majority of patients – 10 of 16 – achieved 50% or greater improvement in one to four OPL sessions. After the first treatment, four patients had roughly a 20% improvement, five were 25%-49% better, three showed 50%-74% clearance, and two patients showed 80% and 100% clearance.

Side effects consisted of 3-5 days of purpura and 1-3 days of local edema. To date, OPL for vascular lesions hasn’t resulted in any scars or in hypo- or hyperpigmentation.

As for the technical details, Dr. Adatto utilized one pass with 50 J/cm² at 10 ms, while Dr. Friedman used a two-pass technique: the first at 34-36 J/cm² at 10 ms, followed by a second at 22-28 J/cm² at 5 ms. Treatment sessions were carried out at 4- to 6-week intervals.

In response to audience questions, Dr. Adatto said that his anecdotal experience has been that once a patient achieves greater than about 50% improvement, be it with a single OPL treatment session or after three, the therapeutic gain of additional sessions is smaller than with the initial ones.

"You can gain another 10% or so with another session for someone who has 70% improvement, but that’s it. You will reach a plateau," he said.

Dr. Adatto is now planning a similar study using OPL to treat vascular lesions in a pediatric population.

The study was funded by Palomar Medical Technologies. Dr. Adatto has received research funds from and is an adviser to Palomar and numerous other laser and intense pulsed light device manufacturers.

DENVER – The presence of any ST depression in the ECG lead aVL in a patient with significant ST segment elevation in inferior leads is highly sensitive and specific for inferior ST-elevation MI as opposed to pericarditis or early repolarization, Dr. Johanna E. Bischof reported at the annual meeting of the American College of Emergency Physicians.

In her retrospective study of three different patient populations with ST elevation in leads II, III, and/or aVF, the finding of at least 0.25 mm of ST depression in lead aVL had 99% sensitivity and 100% specificity for inferior STEMI.

"It’s more sensitive than traditional ST elevation intervention criteria, and more sensitive and specific than comparing the difference in ST elevation between leads III and II," said Dr. Bischof of Hennepin County Medical Center, Minneapolis.

Numerous non–life-threatening cardiac conditions can provoke ST elevation in the inferior leads in the presence of normal conduction with no left bundle branch block, Wolff-Parkinson-White syndrome, paced rhythm, or left ventricular hypertrophy. She and her coworkers evaluated the significance of any ST depression in aVL in two of these conditions that are often confused with inferior STEMI based upon the ECG: pericarditis and early repolarization.

Her retrospective study included 156 Hennepin County Medical Center patients with confirmed inferior STEMI, 39 patients with pericarditis and 1 mm or more of ST elevation in two or more inferior leads, and 66 Finns with early repolarization and ST elevation in inferior leads. The subjects with early repolarization came from the Finnish Health 2000 Survey, in which ECGs were recorded for nearly 11,000 asymptomatic adults.

Of the 156 patients with confirmed inferior STEMI, 155 had ST depression in aVL. Not one of the patients with ST elevation in inferior leads and pericarditis or early repolarization did.

Only 86% of patients with a true inferior STEMI met traditional intervention criteria for STEMI. That means 14% of them might not have gotten to the cardiac catheterization promptly. Using the novel ECG criterion of ST depression in aVL, everyone with an inferior STEMI would have been sent to the cath lab straight away.

Moreover, based upon the finding of ST elevation in inferior leads, 49% of patients in the pericarditis group would have been sent to the cath lab for what would have turned out to be a negative angiogram. With application of the new finding regarding the clinical significance of any ST depression in aVL, none of the patients with pericarditis would have gone to the cath lab, Dr. Bischof continued.

When the degree of ST elevation in lead III exceeds that in lead II, it has traditionally been thought to be more suggestive of inferior STEMI, whereas ST elevation in lead II that’s greater than in lead III is more often thought of as pericarditis. But in Dr. Bischof’s study, only 87% of patients with confirmed inferior STEMI had greater ST elevation in lead III than II. In the pericarditis group, 98% of patients had more ST elevation in II than III. And in subjects with early repolarization, it was roughly 50/50 as to which lead had greater ST elevation.

Senior emergency medicine physicians in the audience called Dr. Bischof’s study "fabulous," adding that they’d like to see the study expanded to include larger numbers of pericarditis patients just to be sure of those excellent sensitivity and specificity figures.

"Truly, if we could take this finding out and utilize it in the ED it would make things very easy for us," one physician commented.

Dr. Bischof reported having no financial conflicts.

DENVER – The presence of any ST depression in the ECG lead aVL in a patient with significant ST segment elevation in inferior leads is highly sensitive and specific for inferior ST-elevation MI as opposed to pericarditis or early repolarization, Dr. Johanna E. Bischof reported at the annual meeting of the American College of Emergency Physicians.

In her retrospective study of three different patient populations with ST elevation in leads II, III, and/or aVF, the finding of at least 0.25 mm of ST depression in lead aVL had 99% sensitivity and 100% specificity for inferior STEMI.

"It’s more sensitive than traditional ST elevation intervention criteria, and more sensitive and specific than comparing the difference in ST elevation between leads III and II," said Dr. Bischof of Hennepin County Medical Center, Minneapolis.

Numerous non–life-threatening cardiac conditions can provoke ST elevation in the inferior leads in the presence of normal conduction with no left bundle branch block, Wolff-Parkinson-White syndrome, paced rhythm, or left ventricular hypertrophy. She and her coworkers evaluated the significance of any ST depression in aVL in two of these conditions that are often confused with inferior STEMI based upon the ECG: pericarditis and early repolarization.

Her retrospective study included 156 Hennepin County Medical Center patients with confirmed inferior STEMI, 39 patients with pericarditis and 1 mm or more of ST elevation in two or more inferior leads, and 66 Finns with early repolarization and ST elevation in inferior leads. The subjects with early repolarization came from the Finnish Health 2000 Survey, in which ECGs were recorded for nearly 11,000 asymptomatic adults.

Of the 156 patients with confirmed inferior STEMI, 155 had ST depression in aVL. Not one of the patients with ST elevation in inferior leads and pericarditis or early repolarization did.

Only 86% of patients with a true inferior STEMI met traditional intervention criteria for STEMI. That means 14% of them might not have gotten to the cardiac catheterization promptly. Using the novel ECG criterion of ST depression in aVL, everyone with an inferior STEMI would have been sent to the cath lab straight away.

Moreover, based upon the finding of ST elevation in inferior leads, 49% of patients in the pericarditis group would have been sent to the cath lab for what would have turned out to be a negative angiogram. With application of the new finding regarding the clinical significance of any ST depression in aVL, none of the patients with pericarditis would have gone to the cath lab, Dr. Bischof continued.

When the degree of ST elevation in lead III exceeds that in lead II, it has traditionally been thought to be more suggestive of inferior STEMI, whereas ST elevation in lead II that’s greater than in lead III is more often thought of as pericarditis. But in Dr. Bischof’s study, only 87% of patients with confirmed inferior STEMI had greater ST elevation in lead III than II. In the pericarditis group, 98% of patients had more ST elevation in II than III. And in subjects with early repolarization, it was roughly 50/50 as to which lead had greater ST elevation.

Senior emergency medicine physicians in the audience called Dr. Bischof’s study "fabulous," adding that they’d like to see the study expanded to include larger numbers of pericarditis patients just to be sure of those excellent sensitivity and specificity figures.

"Truly, if we could take this finding out and utilize it in the ED it would make things very easy for us," one physician commented.

Dr. Bischof reported having no financial conflicts.

DENVER – The presence of any ST depression in the ECG lead aVL in a patient with significant ST segment elevation in inferior leads is highly sensitive and specific for inferior ST-elevation MI as opposed to pericarditis or early repolarization, Dr. Johanna E. Bischof reported at the annual meeting of the American College of Emergency Physicians.

In her retrospective study of three different patient populations with ST elevation in leads II, III, and/or aVF, the finding of at least 0.25 mm of ST depression in lead aVL had 99% sensitivity and 100% specificity for inferior STEMI.

"It’s more sensitive than traditional ST elevation intervention criteria, and more sensitive and specific than comparing the difference in ST elevation between leads III and II," said Dr. Bischof of Hennepin County Medical Center, Minneapolis.

Numerous non–life-threatening cardiac conditions can provoke ST elevation in the inferior leads in the presence of normal conduction with no left bundle branch block, Wolff-Parkinson-White syndrome, paced rhythm, or left ventricular hypertrophy. She and her coworkers evaluated the significance of any ST depression in aVL in two of these conditions that are often confused with inferior STEMI based upon the ECG: pericarditis and early repolarization.

Her retrospective study included 156 Hennepin County Medical Center patients with confirmed inferior STEMI, 39 patients with pericarditis and 1 mm or more of ST elevation in two or more inferior leads, and 66 Finns with early repolarization and ST elevation in inferior leads. The subjects with early repolarization came from the Finnish Health 2000 Survey, in which ECGs were recorded for nearly 11,000 asymptomatic adults.

Of the 156 patients with confirmed inferior STEMI, 155 had ST depression in aVL. Not one of the patients with ST elevation in inferior leads and pericarditis or early repolarization did.

Only 86% of patients with a true inferior STEMI met traditional intervention criteria for STEMI. That means 14% of them might not have gotten to the cardiac catheterization promptly. Using the novel ECG criterion of ST depression in aVL, everyone with an inferior STEMI would have been sent to the cath lab straight away.

Moreover, based upon the finding of ST elevation in inferior leads, 49% of patients in the pericarditis group would have been sent to the cath lab for what would have turned out to be a negative angiogram. With application of the new finding regarding the clinical significance of any ST depression in aVL, none of the patients with pericarditis would have gone to the cath lab, Dr. Bischof continued.

When the degree of ST elevation in lead III exceeds that in lead II, it has traditionally been thought to be more suggestive of inferior STEMI, whereas ST elevation in lead II that’s greater than in lead III is more often thought of as pericarditis. But in Dr. Bischof’s study, only 87% of patients with confirmed inferior STEMI had greater ST elevation in lead III than II. In the pericarditis group, 98% of patients had more ST elevation in II than III. And in subjects with early repolarization, it was roughly 50/50 as to which lead had greater ST elevation.

Senior emergency medicine physicians in the audience called Dr. Bischof’s study "fabulous," adding that they’d like to see the study expanded to include larger numbers of pericarditis patients just to be sure of those excellent sensitivity and specificity figures.

"Truly, if we could take this finding out and utilize it in the ED it would make things very easy for us," one physician commented.

Dr. Bischof reported having no financial conflicts.

LOS ANGELES – Cooling to 32° C in comatose survivors of out-of-hospital cardiac arrest secondary to a shockable rhythm yielded markedly better outcomes than did cooling to 34° C in a pilot randomized trial.

Eight of 13 patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia who were cooled to 32° C (89.6° F) were alive and free of severe dependence 6 months later, compared with just 2 of 13 patients cooled to 34° C (93.2° F).

Bruce Jancin/IMNG Medical Media

None of 10 study participants whose initial rhythm was asystole survived longer than 1 month regardless of which cooling level they received, Dr. Esteban Lopez-de-Sa reported at the annual scientific sessions of the American Heart Association.

Clinical seizures occurred during the first week post cardiac arrest in only 1 of 18 patients cooled at 32° C, compared with 11 of 18 patients cooled to 34° C. On the other hand, seven patients assigned to cooling at 32° developed bradycardia in the first week, compared with two patients cooled to 34°, noted Dr. Lopez-de-Sa, head of the cardiac critical care unit and clinical cardiology at La Paz University Hospital in Madrid.

This randomized trial helps answer an important question: how low to go with therapeutic hypothermia? Current American Heart Association guidelines recommend that comatose survivors of out-of-hospital cardiac arrest undergo therapeutic hypothermia at 32-34° C for 12-24 hours, but the guidelines don’t specify which temperature is better because data have been lacking.

Participants in the Spanish study had a median Glasgow Coma Scale score of 3 upon admission. They were maintained at their assigned target temperature for 24 hours using a feedback device before undergoing 12-24 hours of controlled rewarming.

Dr. Lopez-de-Sa observed that patients successfully resuscitated after out-of-hospital cardiac arrest often have terrible neurologic outcomes, so the 62% rate of survival without severe dependence at 6 months seen in comatose patients with a shockable initial rhythm who were cooled at 32° C in this study is quite encouraging. Freedom from severe dependence was defined as a Barthel Index score of 60 or more out of a possible 100, indicative of an ability to independently perform essential personal care.

Patients were initially cooled with intravenous cold saline. Then they had a catheter placed in the inferior vena cava through a femoral vein attached to the Thermogard XP Temperature Management System manufactured by ZOLL Medical.

Discussant Dr. Graham Nichol noted that many different methods for induction of therapeutic hypothermia exist, including cold water immersion, surface blankets, ice packs, intranasal evaporative cooling, intravenous saline, and intraperitoneal cooling. But no medical device is FDA approved for the induction of hypothermia following resuscitation from cardiac arrest.

"The optimal duration of therapeutic hypothermia, method, and the benefit in the field or in patients with a rhythm other than VF [ventricular fibrillation] remain unclear. I would offer an analogy: For hypothermia in cardiac arrest, ... we are where we were in the 1980s with thrombolytic therapy for myocardial infarction. Most clinicians believe that it works, but there are lots of unanswered questions about timing, dose, and duration," said Dr. Nichol, professor of medicine and director of the University of Washington–Harborview Center for Prehospital Emergency Care, Seattle.

Discussant Dr. Douglas P. Zipes observed that VF and pulseless VT [ventricular tachycardia] are declining as causes of cardiac arrest. Meanwhile, asystole and pulseless electrical activity represent a growing percentage of the cardiac arrest population.

"It’s very distressing that none of the patients in either group who had asystole survived," commented Dr. Zipes, professor emeritus of medicine at Indiana University, Indianapolis.

Dr. Lopez-de-Sa said he believes the therapeutic hypothermia success rate can be improved further in patients with shockable rhythms as well as in those with electromechanical dissociation.

"Probably we need to go to lower temperatures and for longer periods," according to the cardiologist.

Indeed, the superior results seen with cooling to 32° C in the Spanish study may have been due in part to the fact that patients assigned to lower cooling spent more total time in hypothermia, since it took longer to get to their target temperature, he continued.

Animal models indicate that for every 1° C drop in temperature there’s a 6% reduction in cerebral metabolic rate. So lower is probably better in terms of neuroprotection, but only to a point. And that point is 30° C, below which there is a risk of triggering arrhythmias and coagulopathies. Dr. Lopez-de-Sa said that based upon the successful pilot study, he and his coinvestigators are planning a much larger randomized trial, probably comparing 33° C to 31° C.

Simultaneous with Dr. Lopez-de-Sa’s presentation at the meeting, the study findings were published online (Circulation 2012 Nov. 6 [doi: 10.1161/circulationaha.112.136408]).

The study was funded by La Paz University Hospital. Dr. Lopez-de-Sa reported having no financial conflicts. Dr. Nichol receives research funding from Medtronic, ZOLL, Physio-Control, and Cardiac Science.

LOS ANGELES – Cooling to 32° C in comatose survivors of out-of-hospital cardiac arrest secondary to a shockable rhythm yielded markedly better outcomes than did cooling to 34° C in a pilot randomized trial.

Eight of 13 patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia who were cooled to 32° C (89.6° F) were alive and free of severe dependence 6 months later, compared with just 2 of 13 patients cooled to 34° C (93.2° F).

Bruce Jancin/IMNG Medical Media

None of 10 study participants whose initial rhythm was asystole survived longer than 1 month regardless of which cooling level they received, Dr. Esteban Lopez-de-Sa reported at the annual scientific sessions of the American Heart Association.

Clinical seizures occurred during the first week post cardiac arrest in only 1 of 18 patients cooled at 32° C, compared with 11 of 18 patients cooled to 34° C. On the other hand, seven patients assigned to cooling at 32° developed bradycardia in the first week, compared with two patients cooled to 34°, noted Dr. Lopez-de-Sa, head of the cardiac critical care unit and clinical cardiology at La Paz University Hospital in Madrid.

This randomized trial helps answer an important question: how low to go with therapeutic hypothermia? Current American Heart Association guidelines recommend that comatose survivors of out-of-hospital cardiac arrest undergo therapeutic hypothermia at 32-34° C for 12-24 hours, but the guidelines don’t specify which temperature is better because data have been lacking.

Participants in the Spanish study had a median Glasgow Coma Scale score of 3 upon admission. They were maintained at their assigned target temperature for 24 hours using a feedback device before undergoing 12-24 hours of controlled rewarming.

Dr. Lopez-de-Sa observed that patients successfully resuscitated after out-of-hospital cardiac arrest often have terrible neurologic outcomes, so the 62% rate of survival without severe dependence at 6 months seen in comatose patients with a shockable initial rhythm who were cooled at 32° C in this study is quite encouraging. Freedom from severe dependence was defined as a Barthel Index score of 60 or more out of a possible 100, indicative of an ability to independently perform essential personal care.

Patients were initially cooled with intravenous cold saline. Then they had a catheter placed in the inferior vena cava through a femoral vein attached to the Thermogard XP Temperature Management System manufactured by ZOLL Medical.

Discussant Dr. Graham Nichol noted that many different methods for induction of therapeutic hypothermia exist, including cold water immersion, surface blankets, ice packs, intranasal evaporative cooling, intravenous saline, and intraperitoneal cooling. But no medical device is FDA approved for the induction of hypothermia following resuscitation from cardiac arrest.

"The optimal duration of therapeutic hypothermia, method, and the benefit in the field or in patients with a rhythm other than VF [ventricular fibrillation] remain unclear. I would offer an analogy: For hypothermia in cardiac arrest, ... we are where we were in the 1980s with thrombolytic therapy for myocardial infarction. Most clinicians believe that it works, but there are lots of unanswered questions about timing, dose, and duration," said Dr. Nichol, professor of medicine and director of the University of Washington–Harborview Center for Prehospital Emergency Care, Seattle.

Discussant Dr. Douglas P. Zipes observed that VF and pulseless VT [ventricular tachycardia] are declining as causes of cardiac arrest. Meanwhile, asystole and pulseless electrical activity represent a growing percentage of the cardiac arrest population.

"It’s very distressing that none of the patients in either group who had asystole survived," commented Dr. Zipes, professor emeritus of medicine at Indiana University, Indianapolis.

Dr. Lopez-de-Sa said he believes the therapeutic hypothermia success rate can be improved further in patients with shockable rhythms as well as in those with electromechanical dissociation.

"Probably we need to go to lower temperatures and for longer periods," according to the cardiologist.

Indeed, the superior results seen with cooling to 32° C in the Spanish study may have been due in part to the fact that patients assigned to lower cooling spent more total time in hypothermia, since it took longer to get to their target temperature, he continued.

Animal models indicate that for every 1° C drop in temperature there’s a 6% reduction in cerebral metabolic rate. So lower is probably better in terms of neuroprotection, but only to a point. And that point is 30° C, below which there is a risk of triggering arrhythmias and coagulopathies. Dr. Lopez-de-Sa said that based upon the successful pilot study, he and his coinvestigators are planning a much larger randomized trial, probably comparing 33° C to 31° C.

Simultaneous with Dr. Lopez-de-Sa’s presentation at the meeting, the study findings were published online (Circulation 2012 Nov. 6 [doi: 10.1161/circulationaha.112.136408]).

The study was funded by La Paz University Hospital. Dr. Lopez-de-Sa reported having no financial conflicts. Dr. Nichol receives research funding from Medtronic, ZOLL, Physio-Control, and Cardiac Science.

LOS ANGELES – Cooling to 32° C in comatose survivors of out-of-hospital cardiac arrest secondary to a shockable rhythm yielded markedly better outcomes than did cooling to 34° C in a pilot randomized trial.

Eight of 13 patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia who were cooled to 32° C (89.6° F) were alive and free of severe dependence 6 months later, compared with just 2 of 13 patients cooled to 34° C (93.2° F).

Bruce Jancin/IMNG Medical Media

None of 10 study participants whose initial rhythm was asystole survived longer than 1 month regardless of which cooling level they received, Dr. Esteban Lopez-de-Sa reported at the annual scientific sessions of the American Heart Association.

Clinical seizures occurred during the first week post cardiac arrest in only 1 of 18 patients cooled at 32° C, compared with 11 of 18 patients cooled to 34° C. On the other hand, seven patients assigned to cooling at 32° developed bradycardia in the first week, compared with two patients cooled to 34°, noted Dr. Lopez-de-Sa, head of the cardiac critical care unit and clinical cardiology at La Paz University Hospital in Madrid.

This randomized trial helps answer an important question: how low to go with therapeutic hypothermia? Current American Heart Association guidelines recommend that comatose survivors of out-of-hospital cardiac arrest undergo therapeutic hypothermia at 32-34° C for 12-24 hours, but the guidelines don’t specify which temperature is better because data have been lacking.

Participants in the Spanish study had a median Glasgow Coma Scale score of 3 upon admission. They were maintained at their assigned target temperature for 24 hours using a feedback device before undergoing 12-24 hours of controlled rewarming.

Dr. Lopez-de-Sa observed that patients successfully resuscitated after out-of-hospital cardiac arrest often have terrible neurologic outcomes, so the 62% rate of survival without severe dependence at 6 months seen in comatose patients with a shockable initial rhythm who were cooled at 32° C in this study is quite encouraging. Freedom from severe dependence was defined as a Barthel Index score of 60 or more out of a possible 100, indicative of an ability to independently perform essential personal care.

Patients were initially cooled with intravenous cold saline. Then they had a catheter placed in the inferior vena cava through a femoral vein attached to the Thermogard XP Temperature Management System manufactured by ZOLL Medical.

Discussant Dr. Graham Nichol noted that many different methods for induction of therapeutic hypothermia exist, including cold water immersion, surface blankets, ice packs, intranasal evaporative cooling, intravenous saline, and intraperitoneal cooling. But no medical device is FDA approved for the induction of hypothermia following resuscitation from cardiac arrest.

"The optimal duration of therapeutic hypothermia, method, and the benefit in the field or in patients with a rhythm other than VF [ventricular fibrillation] remain unclear. I would offer an analogy: For hypothermia in cardiac arrest, ... we are where we were in the 1980s with thrombolytic therapy for myocardial infarction. Most clinicians believe that it works, but there are lots of unanswered questions about timing, dose, and duration," said Dr. Nichol, professor of medicine and director of the University of Washington–Harborview Center for Prehospital Emergency Care, Seattle.

Discussant Dr. Douglas P. Zipes observed that VF and pulseless VT [ventricular tachycardia] are declining as causes of cardiac arrest. Meanwhile, asystole and pulseless electrical activity represent a growing percentage of the cardiac arrest population.

"It’s very distressing that none of the patients in either group who had asystole survived," commented Dr. Zipes, professor emeritus of medicine at Indiana University, Indianapolis.

Dr. Lopez-de-Sa said he believes the therapeutic hypothermia success rate can be improved further in patients with shockable rhythms as well as in those with electromechanical dissociation.

"Probably we need to go to lower temperatures and for longer periods," according to the cardiologist.

Indeed, the superior results seen with cooling to 32° C in the Spanish study may have been due in part to the fact that patients assigned to lower cooling spent more total time in hypothermia, since it took longer to get to their target temperature, he continued.

Animal models indicate that for every 1° C drop in temperature there’s a 6% reduction in cerebral metabolic rate. So lower is probably better in terms of neuroprotection, but only to a point. And that point is 30° C, below which there is a risk of triggering arrhythmias and coagulopathies. Dr. Lopez-de-Sa said that based upon the successful pilot study, he and his coinvestigators are planning a much larger randomized trial, probably comparing 33° C to 31° C.

Simultaneous with Dr. Lopez-de-Sa’s presentation at the meeting, the study findings were published online (Circulation 2012 Nov. 6 [doi: 10.1161/circulationaha.112.136408]).

The study was funded by La Paz University Hospital. Dr. Lopez-de-Sa reported having no financial conflicts. Dr. Nichol receives research funding from Medtronic, ZOLL, Physio-Control, and Cardiac Science.

PRAGUE – The investigational anti-interleukin-17A biologic agent secukinumab holds particular promise for the treatment of psoriasis in two of its most challenging, tough-to-tame manifestations: hand and foot psoriasis and nail involvement, a study has shown.

A post hoc analysis of a previously reported phase II, double-blind, placebo-controlled, 12-week dose-finding study in 404 patients with moderate to severe plaque psoriasis focused in part on the 131 subjects with hand and/or foot involvement. The same regimen that achieved the best outcomes in the main study – 150 mg of secukinumab given subcutaneously at weeks 0, 1, 2, and 4 – showed the greatest beneficial effect for hand and foot psoriasis, Dr. Carle Paul reported at the annual congress of the European Academy of Dermatology and Venereology.

Photo credit: Elsevier 2009

Fifty-four percent of patients randomized to this optimal secukinumab dosing regimen achieved a positive investigator global response of their moderate to severe hand and foot psoriasis at week 12 compared with 19% assigned to placebo. An investigator global response required at least a 2-point improvement on a 5-point scale along with a score of 0 or 1, meaning clear or only minimal disease, explained Dr. Paul, a dermatologist at the University of Toulouse (France).

The PASI 75 and PASI 90 rates in patients with hand and foot psoriasis – that is, the percentage of patients with at least a 75% or 90% improvement over baseline scores on the Psoriasis Area and Severity Index – were similar to the 55% and 32% rates observed in the overall study population, he added.

The phase II study also included 304 patients with nail psoriasis. At week 12, those patients treated with secukinumab at weeks 0, 1, 2, and 4 showed a mean 19% improvement on a composite fingernail involvement score, compared with a 14% worsening with placebo.

These findings are especially encouraging because hand, foot, and nail psoriasis affect an estimated 10%-55% of all psoriasis patients. Involvement at these sites causes considerable functional disability, including difficulty in walking and using the hands. In addition, hand, foot, and nail psoriasis are notoriously difficult to treat.

Secukinumab’s side effect pattern in the large phase II study was similar to that for placebo. Definitive safety and efficacy results will come from ongoing pivotal phase III clinical trials totaling more than 3,000 psoriasis patients worldwide. The results are anticipated next year.

In addition to being used for psoriasis, secukinumab is being developed as a novel treatment for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Ongoing phase III studies are expected to report results in 2014. Also, phase II studies of secukinumab for multiple sclerosis are underway.

Secukinumab is a fully human anti-interleukin-17A monoclonal antibody being developed by Novartis.

The phase II study and post hoc analysis were sponsored by Novartis. Dr. Paul is a recipient of research grants from and is a consultant to the company.

PRAGUE – The investigational anti-interleukin-17A biologic agent secukinumab holds particular promise for the treatment of psoriasis in two of its most challenging, tough-to-tame manifestations: hand and foot psoriasis and nail involvement, a study has shown.

A post hoc analysis of a previously reported phase II, double-blind, placebo-controlled, 12-week dose-finding study in 404 patients with moderate to severe plaque psoriasis focused in part on the 131 subjects with hand and/or foot involvement. The same regimen that achieved the best outcomes in the main study – 150 mg of secukinumab given subcutaneously at weeks 0, 1, 2, and 4 – showed the greatest beneficial effect for hand and foot psoriasis, Dr. Carle Paul reported at the annual congress of the European Academy of Dermatology and Venereology.

Photo credit: Elsevier 2009

Fifty-four percent of patients randomized to this optimal secukinumab dosing regimen achieved a positive investigator global response of their moderate to severe hand and foot psoriasis at week 12 compared with 19% assigned to placebo. An investigator global response required at least a 2-point improvement on a 5-point scale along with a score of 0 or 1, meaning clear or only minimal disease, explained Dr. Paul, a dermatologist at the University of Toulouse (France).

The PASI 75 and PASI 90 rates in patients with hand and foot psoriasis – that is, the percentage of patients with at least a 75% or 90% improvement over baseline scores on the Psoriasis Area and Severity Index – were similar to the 55% and 32% rates observed in the overall study population, he added.

The phase II study also included 304 patients with nail psoriasis. At week 12, those patients treated with secukinumab at weeks 0, 1, 2, and 4 showed a mean 19% improvement on a composite fingernail involvement score, compared with a 14% worsening with placebo.

These findings are especially encouraging because hand, foot, and nail psoriasis affect an estimated 10%-55% of all psoriasis patients. Involvement at these sites causes considerable functional disability, including difficulty in walking and using the hands. In addition, hand, foot, and nail psoriasis are notoriously difficult to treat.

Secukinumab’s side effect pattern in the large phase II study was similar to that for placebo. Definitive safety and efficacy results will come from ongoing pivotal phase III clinical trials totaling more than 3,000 psoriasis patients worldwide. The results are anticipated next year.

In addition to being used for psoriasis, secukinumab is being developed as a novel treatment for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Ongoing phase III studies are expected to report results in 2014. Also, phase II studies of secukinumab for multiple sclerosis are underway.

Secukinumab is a fully human anti-interleukin-17A monoclonal antibody being developed by Novartis.

The phase II study and post hoc analysis were sponsored by Novartis. Dr. Paul is a recipient of research grants from and is a consultant to the company.

PRAGUE – The investigational anti-interleukin-17A biologic agent secukinumab holds particular promise for the treatment of psoriasis in two of its most challenging, tough-to-tame manifestations: hand and foot psoriasis and nail involvement, a study has shown.

A post hoc analysis of a previously reported phase II, double-blind, placebo-controlled, 12-week dose-finding study in 404 patients with moderate to severe plaque psoriasis focused in part on the 131 subjects with hand and/or foot involvement. The same regimen that achieved the best outcomes in the main study – 150 mg of secukinumab given subcutaneously at weeks 0, 1, 2, and 4 – showed the greatest beneficial effect for hand and foot psoriasis, Dr. Carle Paul reported at the annual congress of the European Academy of Dermatology and Venereology.

Photo credit: Elsevier 2009

Fifty-four percent of patients randomized to this optimal secukinumab dosing regimen achieved a positive investigator global response of their moderate to severe hand and foot psoriasis at week 12 compared with 19% assigned to placebo. An investigator global response required at least a 2-point improvement on a 5-point scale along with a score of 0 or 1, meaning clear or only minimal disease, explained Dr. Paul, a dermatologist at the University of Toulouse (France).

The PASI 75 and PASI 90 rates in patients with hand and foot psoriasis – that is, the percentage of patients with at least a 75% or 90% improvement over baseline scores on the Psoriasis Area and Severity Index – were similar to the 55% and 32% rates observed in the overall study population, he added.

The phase II study also included 304 patients with nail psoriasis. At week 12, those patients treated with secukinumab at weeks 0, 1, 2, and 4 showed a mean 19% improvement on a composite fingernail involvement score, compared with a 14% worsening with placebo.

These findings are especially encouraging because hand, foot, and nail psoriasis affect an estimated 10%-55% of all psoriasis patients. Involvement at these sites causes considerable functional disability, including difficulty in walking and using the hands. In addition, hand, foot, and nail psoriasis are notoriously difficult to treat.

Secukinumab’s side effect pattern in the large phase II study was similar to that for placebo. Definitive safety and efficacy results will come from ongoing pivotal phase III clinical trials totaling more than 3,000 psoriasis patients worldwide. The results are anticipated next year.

In addition to being used for psoriasis, secukinumab is being developed as a novel treatment for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Ongoing phase III studies are expected to report results in 2014. Also, phase II studies of secukinumab for multiple sclerosis are underway.

Secukinumab is a fully human anti-interleukin-17A monoclonal antibody being developed by Novartis.

The phase II study and post hoc analysis were sponsored by Novartis. Dr. Paul is a recipient of research grants from and is a consultant to the company.

PRAGUE – A handful of drugs are backed by solid-quality evidence for the treatment of hidradenitis suppurativa, although to date no form of therapy is approved for this indication.

Topping the list are the tumor necrosis factor (TNF)-alpha inhibitors. They have a plausible mechanism of benefit in hidradenitis suppurativa (HS). They’ve also demonstrated effectiveness for this common inflammatory skin disease in randomized, placebo-controlled clinical trials, Dr. Gregor B. Jemec said at the annual congress of the European Academy of Dermatology and Venereology.

In addition, one older randomized trial suggests that topical clindamycin is effective, mainly in milder cases. The most promising antibiotic regimen, consisting of oral clindamycin at 300 mg twice daily plus rifampicin at 600 mg daily, has not been studied in a randomized trial. But several large, rigorous case series have demonstrated "dramatic improvement" in response to the combination, according to Dr. Jemec of the University of Copenhagen.

TNF Inhibitors

The discovery that anti-TNF therapy is effective for HS was a serendipitous finding that occurred when physicians noted marked improvement in the skin disease in a patient taking infliximab for Crohn’s disease. The biologic plausibility of the observed benefit is underscored by the fact that TNF levels are actually more elevated in patients with HS than in those with psoriasis, Dr. Jemec said.

Infliximab missed its primary efficacy end point of clear or almost clear in a 38-patient randomized trial, but it did hit several clinically important secondary end points, including pain reduction and improved quality of life (J. Am. Acad. Dermatol. 2010;62:205-17).

On the other hand, etanercept showed no benefit in a 20-patient pilot randomized trial (Arch. Dermatol. 2010;146:501-4).

By far the best studied TNF inhibitor in HS is adalimumab (Humira). It is the subject of two ongoing, pivotal phase III randomized, double-blind, placebo-controlled, multinational clinical trials aimed at winning adalimumab regulatory approval as the first-ever drug indicated for the treatment of HS.

Last year, Dr. Alexa B. Kimball of Harvard Medical School, Boston, presented the primary end point of a 16-week, randomized, double-blind phase II clinical trial involving 154 patients with HS who were placed on adalimumab 40 mg weekly, adalimumab 40 mg every other week, or placebo. At week 16, a Physician Global Assessment of clear, minimal, or mild disease with at least a 2-grade improvement over baseline was documented in 23.5% of patients on placebo, 21.2% of those on alternate-week adalimumab, and 49% of those on adalimumab 40 mg every week.

With a therapy that achieves clear or close to it in only half of treated patients, other end points take on added importance. At this year’s EADV (European Academy of Dermatology and Venereology) congress, Dr. Kimball and others presented several key secondary outcomes from the phase II study. One involved pain, a particularly prominent feature in HS. From a mean baseline pain score of 52 on a 0-100 visual analog scale, the weekly adalimumab group’s score dropped by a placebo-subtracted 15.8 points by week 2, 18.4 points at week 4, 11.7 points by week 8, 20.7 points at week 12, and by 11 points at week 20.

The minimum clinically important difference, predefined as at least a 15.4-point improvement in self-rated pain scores, occurred in 33% of the weekly adalimumab group, compared with 15% of patients on placebo at week 2. By week 12 this end point had been achieved in 63% of the weekly adalimumab group and 26% of the placebo group. Adalimumab every other week didn’t consistently improve pain relative to placebo, she reported.

Dr. Ulrich Mrowietz reported separately that the impaired work productivity that often affects patients with HS was significantly lessened by treatment with adalimumab 40 mg weekly. Total work productivity impairment as measured at week 16 by the Work Productivity and Activity Impairment Questionnaire improved by a mean of 15 points in the weekly adalimumab group while worsening by 2.7 points with placebo; the net 17.7-unit difference exceeded the minimum clinically important difference threshold of 16.2 points.

Patients assigned to weekly adalimumab also experienced significantly improved scores on the Dermatology Life Quality Index beginning on week 2 and lasting throughout the 16-week study. At week 16, for example, they enjoyed a mean 5.5-point improvement relative to baseline, compared with a 1.6-point improvement with placebo, according to Dr. Mrowietz of University Medical Center in Kiel, Germany.

Oral Antibiotics

Dr. Jemec highlighted as particularly impressive a retrospective French case series of 116 patients with severe HS treated using the combination of clindamycin 300 mg twice daily and rifampicin 600 mg daily. Severity scores decreased as a result by 50%. Seven percent of patients dropped the therapy due to diarrhea (Dermatology 2009;219:148-54).

Two smaller published case series have boosted to 164 the total number of HS patients treated with similarly "dramatic" results, noted Dr. Jemec. He was an investigator in one of these studies, in which 10 weeks on the antibiotic combination resulted in at least partial improvement in 28 of 34 patients and total remission in 16 (47%). Eight of the 16 relapsed after a mean of 5 months (Dermatology 2009;219:143-7).

Elsevier Inc.

Another approach has involved an intensive oral regimen of broad-spectrum antibiotics consisting of rifampin at 10 mg/kg once daily, moxifloxacin at 400 mg/day, and metronidazole at 500 mg three times daily. In a series of 28 consecutive patients with long-standing refractory HS, French investigators prescribed this regimen for 6-12 weeks before switching to consolidation therapy with rifampin and moxifloxacin for 6 more weeks. Complete remission was achieved in 16 of the 28 patients (Dermatology 2011;222:49-58).

"This therapy has yielded remarkably good results in terms of clearance and maintenance of clearance," commented Dr. Jemec.

The main side effects were diarrhea, a complaint in nearly two-thirds of patients, and vaginal candidiasis, which occurred in one-third of treated women.

Topical Clindamycin

Dr. Jemec was a coinvestigator in an early double-blind, 46-patient study that established topical clindamycin as being as effective as oral tetracycline in patients with mild disease (J. Am. Acad. Dermatol. 1998;39:971-4).

Beyond this point, the strength of evidence for proposed HS therapies tails off considerably. But Dr. Jemec deemed a couple of agents worthy of mention on the basis of intriguing yet less than persuasive supporting data:

• Acitretin. In a case series of 12 HS patients treated for 9-12 months at the relatively high dose of 0.6 mg/kg per day of acitretin, with stringent 4-year follow-up, all patients went into remission. In eight patients, the remission lasted for at least 1 year, including a single patient who has been in remission for 4 years and counting (Br. J. Dermatol. 2011;164:170-5). "Remarkable," Dr. Jemec commented.

• Dapsone. This drug is frequently reported anecdotally as being useful in HS, typically with an n-of-1 experience. Dr. Jemec and his coworkers recently published a case series of 24 treated patients, 9 of whom (38%) showed improvement (Dermatology 2011;222:342-6). None of the four severely affected patients improved, however. It was Dr. Jemec’s impression that the degree of improvement was less than he’s seen with combined oral clindamycin and rifampicin. He’d like to see a head-to-head comparison before reaching a final judgment as to a possible role for dapsone.

Dr. Jemec has received research grants from and serves as a consultant to Abbott Laboratories, which is developing adalimumab as a treatment for HS, as well as a dozen other pharmaceutical companies. Dr. Mrowietz is a consultant to Abbott, which funded his study, and to other dermatologic pharmaceutical companies.

PRAGUE – A handful of drugs are backed by solid-quality evidence for the treatment of hidradenitis suppurativa, although to date no form of therapy is approved for this indication.

Topping the list are the tumor necrosis factor (TNF)-alpha inhibitors. They have a plausible mechanism of benefit in hidradenitis suppurativa (HS). They’ve also demonstrated effectiveness for this common inflammatory skin disease in randomized, placebo-controlled clinical trials, Dr. Gregor B. Jemec said at the annual congress of the European Academy of Dermatology and Venereology.

In addition, one older randomized trial suggests that topical clindamycin is effective, mainly in milder cases. The most promising antibiotic regimen, consisting of oral clindamycin at 300 mg twice daily plus rifampicin at 600 mg daily, has not been studied in a randomized trial. But several large, rigorous case series have demonstrated "dramatic improvement" in response to the combination, according to Dr. Jemec of the University of Copenhagen.

TNF Inhibitors

The discovery that anti-TNF therapy is effective for HS was a serendipitous finding that occurred when physicians noted marked improvement in the skin disease in a patient taking infliximab for Crohn’s disease. The biologic plausibility of the observed benefit is underscored by the fact that TNF levels are actually more elevated in patients with HS than in those with psoriasis, Dr. Jemec said.

Infliximab missed its primary efficacy end point of clear or almost clear in a 38-patient randomized trial, but it did hit several clinically important secondary end points, including pain reduction and improved quality of life (J. Am. Acad. Dermatol. 2010;62:205-17).

On the other hand, etanercept showed no benefit in a 20-patient pilot randomized trial (Arch. Dermatol. 2010;146:501-4).

By far the best studied TNF inhibitor in HS is adalimumab (Humira). It is the subject of two ongoing, pivotal phase III randomized, double-blind, placebo-controlled, multinational clinical trials aimed at winning adalimumab regulatory approval as the first-ever drug indicated for the treatment of HS.

Last year, Dr. Alexa B. Kimball of Harvard Medical School, Boston, presented the primary end point of a 16-week, randomized, double-blind phase II clinical trial involving 154 patients with HS who were placed on adalimumab 40 mg weekly, adalimumab 40 mg every other week, or placebo. At week 16, a Physician Global Assessment of clear, minimal, or mild disease with at least a 2-grade improvement over baseline was documented in 23.5% of patients on placebo, 21.2% of those on alternate-week adalimumab, and 49% of those on adalimumab 40 mg every week.

With a therapy that achieves clear or close to it in only half of treated patients, other end points take on added importance. At this year’s EADV (European Academy of Dermatology and Venereology) congress, Dr. Kimball and others presented several key secondary outcomes from the phase II study. One involved pain, a particularly prominent feature in HS. From a mean baseline pain score of 52 on a 0-100 visual analog scale, the weekly adalimumab group’s score dropped by a placebo-subtracted 15.8 points by week 2, 18.4 points at week 4, 11.7 points by week 8, 20.7 points at week 12, and by 11 points at week 20.

The minimum clinically important difference, predefined as at least a 15.4-point improvement in self-rated pain scores, occurred in 33% of the weekly adalimumab group, compared with 15% of patients on placebo at week 2. By week 12 this end point had been achieved in 63% of the weekly adalimumab group and 26% of the placebo group. Adalimumab every other week didn’t consistently improve pain relative to placebo, she reported.

Dr. Ulrich Mrowietz reported separately that the impaired work productivity that often affects patients with HS was significantly lessened by treatment with adalimumab 40 mg weekly. Total work productivity impairment as measured at week 16 by the Work Productivity and Activity Impairment Questionnaire improved by a mean of 15 points in the weekly adalimumab group while worsening by 2.7 points with placebo; the net 17.7-unit difference exceeded the minimum clinically important difference threshold of 16.2 points.

Patients assigned to weekly adalimumab also experienced significantly improved scores on the Dermatology Life Quality Index beginning on week 2 and lasting throughout the 16-week study. At week 16, for example, they enjoyed a mean 5.5-point improvement relative to baseline, compared with a 1.6-point improvement with placebo, according to Dr. Mrowietz of University Medical Center in Kiel, Germany.

Oral Antibiotics

Dr. Jemec highlighted as particularly impressive a retrospective French case series of 116 patients with severe HS treated using the combination of clindamycin 300 mg twice daily and rifampicin 600 mg daily. Severity scores decreased as a result by 50%. Seven percent of patients dropped the therapy due to diarrhea (Dermatology 2009;219:148-54).

Two smaller published case series have boosted to 164 the total number of HS patients treated with similarly "dramatic" results, noted Dr. Jemec. He was an investigator in one of these studies, in which 10 weeks on the antibiotic combination resulted in at least partial improvement in 28 of 34 patients and total remission in 16 (47%). Eight of the 16 relapsed after a mean of 5 months (Dermatology 2009;219:143-7).

Elsevier Inc.

Another approach has involved an intensive oral regimen of broad-spectrum antibiotics consisting of rifampin at 10 mg/kg once daily, moxifloxacin at 400 mg/day, and metronidazole at 500 mg three times daily. In a series of 28 consecutive patients with long-standing refractory HS, French investigators prescribed this regimen for 6-12 weeks before switching to consolidation therapy with rifampin and moxifloxacin for 6 more weeks. Complete remission was achieved in 16 of the 28 patients (Dermatology 2011;222:49-58).

"This therapy has yielded remarkably good results in terms of clearance and maintenance of clearance," commented Dr. Jemec.

The main side effects were diarrhea, a complaint in nearly two-thirds of patients, and vaginal candidiasis, which occurred in one-third of treated women.

Topical Clindamycin

Dr. Jemec was a coinvestigator in an early double-blind, 46-patient study that established topical clindamycin as being as effective as oral tetracycline in patients with mild disease (J. Am. Acad. Dermatol. 1998;39:971-4).

Beyond this point, the strength of evidence for proposed HS therapies tails off considerably. But Dr. Jemec deemed a couple of agents worthy of mention on the basis of intriguing yet less than persuasive supporting data:

• Acitretin. In a case series of 12 HS patients treated for 9-12 months at the relatively high dose of 0.6 mg/kg per day of acitretin, with stringent 4-year follow-up, all patients went into remission. In eight patients, the remission lasted for at least 1 year, including a single patient who has been in remission for 4 years and counting (Br. J. Dermatol. 2011;164:170-5). "Remarkable," Dr. Jemec commented.

• Dapsone. This drug is frequently reported anecdotally as being useful in HS, typically with an n-of-1 experience. Dr. Jemec and his coworkers recently published a case series of 24 treated patients, 9 of whom (38%) showed improvement (Dermatology 2011;222:342-6). None of the four severely affected patients improved, however. It was Dr. Jemec’s impression that the degree of improvement was less than he’s seen with combined oral clindamycin and rifampicin. He’d like to see a head-to-head comparison before reaching a final judgment as to a possible role for dapsone.

Dr. Jemec has received research grants from and serves as a consultant to Abbott Laboratories, which is developing adalimumab as a treatment for HS, as well as a dozen other pharmaceutical companies. Dr. Mrowietz is a consultant to Abbott, which funded his study, and to other dermatologic pharmaceutical companies.

PRAGUE – A handful of drugs are backed by solid-quality evidence for the treatment of hidradenitis suppurativa, although to date no form of therapy is approved for this indication.

Topping the list are the tumor necrosis factor (TNF)-alpha inhibitors. They have a plausible mechanism of benefit in hidradenitis suppurativa (HS). They’ve also demonstrated effectiveness for this common inflammatory skin disease in randomized, placebo-controlled clinical trials, Dr. Gregor B. Jemec said at the annual congress of the European Academy of Dermatology and Venereology.

In addition, one older randomized trial suggests that topical clindamycin is effective, mainly in milder cases. The most promising antibiotic regimen, consisting of oral clindamycin at 300 mg twice daily plus rifampicin at 600 mg daily, has not been studied in a randomized trial. But several large, rigorous case series have demonstrated "dramatic improvement" in response to the combination, according to Dr. Jemec of the University of Copenhagen.

TNF Inhibitors

The discovery that anti-TNF therapy is effective for HS was a serendipitous finding that occurred when physicians noted marked improvement in the skin disease in a patient taking infliximab for Crohn’s disease. The biologic plausibility of the observed benefit is underscored by the fact that TNF levels are actually more elevated in patients with HS than in those with psoriasis, Dr. Jemec said.

Infliximab missed its primary efficacy end point of clear or almost clear in a 38-patient randomized trial, but it did hit several clinically important secondary end points, including pain reduction and improved quality of life (J. Am. Acad. Dermatol. 2010;62:205-17).

On the other hand, etanercept showed no benefit in a 20-patient pilot randomized trial (Arch. Dermatol. 2010;146:501-4).

By far the best studied TNF inhibitor in HS is adalimumab (Humira). It is the subject of two ongoing, pivotal phase III randomized, double-blind, placebo-controlled, multinational clinical trials aimed at winning adalimumab regulatory approval as the first-ever drug indicated for the treatment of HS.

Last year, Dr. Alexa B. Kimball of Harvard Medical School, Boston, presented the primary end point of a 16-week, randomized, double-blind phase II clinical trial involving 154 patients with HS who were placed on adalimumab 40 mg weekly, adalimumab 40 mg every other week, or placebo. At week 16, a Physician Global Assessment of clear, minimal, or mild disease with at least a 2-grade improvement over baseline was documented in 23.5% of patients on placebo, 21.2% of those on alternate-week adalimumab, and 49% of those on adalimumab 40 mg every week.

With a therapy that achieves clear or close to it in only half of treated patients, other end points take on added importance. At this year’s EADV (European Academy of Dermatology and Venereology) congress, Dr. Kimball and others presented several key secondary outcomes from the phase II study. One involved pain, a particularly prominent feature in HS. From a mean baseline pain score of 52 on a 0-100 visual analog scale, the weekly adalimumab group’s score dropped by a placebo-subtracted 15.8 points by week 2, 18.4 points at week 4, 11.7 points by week 8, 20.7 points at week 12, and by 11 points at week 20.

The minimum clinically important difference, predefined as at least a 15.4-point improvement in self-rated pain scores, occurred in 33% of the weekly adalimumab group, compared with 15% of patients on placebo at week 2. By week 12 this end point had been achieved in 63% of the weekly adalimumab group and 26% of the placebo group. Adalimumab every other week didn’t consistently improve pain relative to placebo, she reported.

Dr. Ulrich Mrowietz reported separately that the impaired work productivity that often affects patients with HS was significantly lessened by treatment with adalimumab 40 mg weekly. Total work productivity impairment as measured at week 16 by the Work Productivity and Activity Impairment Questionnaire improved by a mean of 15 points in the weekly adalimumab group while worsening by 2.7 points with placebo; the net 17.7-unit difference exceeded the minimum clinically important difference threshold of 16.2 points.

Patients assigned to weekly adalimumab also experienced significantly improved scores on the Dermatology Life Quality Index beginning on week 2 and lasting throughout the 16-week study. At week 16, for example, they enjoyed a mean 5.5-point improvement relative to baseline, compared with a 1.6-point improvement with placebo, according to Dr. Mrowietz of University Medical Center in Kiel, Germany.

Oral Antibiotics

Dr. Jemec highlighted as particularly impressive a retrospective French case series of 116 patients with severe HS treated using the combination of clindamycin 300 mg twice daily and rifampicin 600 mg daily. Severity scores decreased as a result by 50%. Seven percent of patients dropped the therapy due to diarrhea (Dermatology 2009;219:148-54).

Two smaller published case series have boosted to 164 the total number of HS patients treated with similarly "dramatic" results, noted Dr. Jemec. He was an investigator in one of these studies, in which 10 weeks on the antibiotic combination resulted in at least partial improvement in 28 of 34 patients and total remission in 16 (47%). Eight of the 16 relapsed after a mean of 5 months (Dermatology 2009;219:143-7).

Elsevier Inc.

Another approach has involved an intensive oral regimen of broad-spectrum antibiotics consisting of rifampin at 10 mg/kg once daily, moxifloxacin at 400 mg/day, and metronidazole at 500 mg three times daily. In a series of 28 consecutive patients with long-standing refractory HS, French investigators prescribed this regimen for 6-12 weeks before switching to consolidation therapy with rifampin and moxifloxacin for 6 more weeks. Complete remission was achieved in 16 of the 28 patients (Dermatology 2011;222:49-58).

"This therapy has yielded remarkably good results in terms of clearance and maintenance of clearance," commented Dr. Jemec.

The main side effects were diarrhea, a complaint in nearly two-thirds of patients, and vaginal candidiasis, which occurred in one-third of treated women.

Topical Clindamycin

Dr. Jemec was a coinvestigator in an early double-blind, 46-patient study that established topical clindamycin as being as effective as oral tetracycline in patients with mild disease (J. Am. Acad. Dermatol. 1998;39:971-4).

Beyond this point, the strength of evidence for proposed HS therapies tails off considerably. But Dr. Jemec deemed a couple of agents worthy of mention on the basis of intriguing yet less than persuasive supporting data:

• Acitretin. In a case series of 12 HS patients treated for 9-12 months at the relatively high dose of 0.6 mg/kg per day of acitretin, with stringent 4-year follow-up, all patients went into remission. In eight patients, the remission lasted for at least 1 year, including a single patient who has been in remission for 4 years and counting (Br. J. Dermatol. 2011;164:170-5). "Remarkable," Dr. Jemec commented.

• Dapsone. This drug is frequently reported anecdotally as being useful in HS, typically with an n-of-1 experience. Dr. Jemec and his coworkers recently published a case series of 24 treated patients, 9 of whom (38%) showed improvement (Dermatology 2011;222:342-6). None of the four severely affected patients improved, however. It was Dr. Jemec’s impression that the degree of improvement was less than he’s seen with combined oral clindamycin and rifampicin. He’d like to see a head-to-head comparison before reaching a final judgment as to a possible role for dapsone.

Dr. Jemec has received research grants from and serves as a consultant to Abbott Laboratories, which is developing adalimumab as a treatment for HS, as well as a dozen other pharmaceutical companies. Dr. Mrowietz is a consultant to Abbott, which funded his study, and to other dermatologic pharmaceutical companies.

LOS ANGELES – The recombinant vasoactive peptide hormone serelaxin showed the potential to be a breakthrough therapy for acute heart failure in a phase III randomized trial.

In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin brought greater dyspnea relief than standard treatment plus placebo. It also markedly reduced the risk of worsening heart failure during the index hospitalization, significantly shortened ICU and total hospital lengths of stay, improved biomarkers, and displayed a benign safety profile. Most impressive of all, serelaxin was associated with a highly significant 37% reduction in both cardiovascular and all-cause mortality at follow-up 6 months after administration of a 48-hour infusion, study co-principal investigator Dr. John R. Teerlink reported on Nov. 6 at the annual scientific sessions of the American Heart Association.

These benefits mirror those seen earlier in the phase II Pre-RELAX-AHF study (Lancet 2009;373:1429-39). That study showed an all-cause mortality reduction in the subgroup randomized to the same dose of serelaxin used in the phase III trial, added Dr. Teerlink, professor of medicine at the University of California, San Francisco.

Serelaxin is recombinant human relaxin-2, which is present in both men and women. The hormone rises to pharmacologic levels during pregnancy. During that time, it promotes increased cardiac output, renal blood flow, and arterial compliance.

"Those are exactly the kinds of changes we’d like to see in patients with acute heart failure," Dr. Teerlink explained in describing the rationale for developing the hormone as a novel cardiovascular medication.

Heart failure experts who commented on RELAX-AHF were unanimous in their conviction that the study persuasively demonstrated that serelaxin reduces breathlessness and other signs and symptoms of acute heart failure. They were more cautious regarding the observed mortality benefit.

"My own feeling about this is that it would be very nice to see this finding replicated. If we did replicate this finding it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or lifesaving therapies," said Dr. John McMurray, professor of medical cardiology at the University of Glasgow.

RELAX-AHF was an international double-blind study that enrolled 1,161 patients hospitalized for acute heart failure. All had dyspnea at rest or with minimal exertion, pulmonary congestion, mild to moderate renal insufficiency, elevated brain natriuretic peptide levels, and a systolic blood pressure greater than 125 mm Hg despite having received at least 40 mg of intravenous furosemide or its equivalent shortly before enrollment. Participants were randomized to intravenous serelaxin at 30 mcg/kg per day for 48 hours or placebo on top of standard management.

The results: The serelaxin-treated group experienced a 19% improvement in the primary end point of patient-reported dyspnea to day 5. They also had a 30% reduction in the relative risk of worsening heart failure events up to day 14, despite roughly 25% less use of intravenous diuretics and other vasoactive drugs than in the placebo group. The average length of the initial hospital stay was 9.6 days in the serelaxin group, and nearly a full day longer at 10.5 days in controls. The serelaxin group averaged 3.5 days in the ICU or coronary care unit, 0.4 days less than the placebo group.

They were less likely than controls to experience a significant rise in creatinine or troponin T at day 2, and more likely to have a substantial decrease in NT-proBNP and liver enzymes.

But the head-turning result was the cardiovascular death rate through day 180: 9.5% with placebo compared with 6.0% with serelaxin, for a 37% reduction in risk. The number of patients who needed to be treated with serelaxin for 48 hours in order to prevent one additional cardiovascular death was 29. All-cause mortality was reduced to a similar extent, with an 11.3% rate in controls, compared with 7.3% with serelaxin.

Rates and types of adverse events overall and serious adverse events were similar in the two study arms.

But not all prespecified end points were met. Most important, in Dr. McMurray’s view, was the serelaxin group’s lack of a reduction in rehospitalizations for heart failure or renal failure during 60 days of follow-up. In chronic heart failure, it’s very unusual to see a treatment that improves survival but does not reduce rehospitalization. Also, 6-month mortality was not a prespecified end point in RELAX-AHF. And the mortality conclusions were based on relatively small numbers.

"In acute heart failure in the past, we’ve been famously misled by small numbers," he said, citing the example of vesnarinone, which in its first randomized trial showed a 62% reduction in all-cause mortality that didn’t hold up in a second, much larger trial.

Dr. Milton Packer drew attention to the impressively short time between hospital admission and the start of serelaxin, which averaged less than 8 hours.

"No trial has ever pulled that off before. And here’s the thing that’s really exciting about RELAX-AHF: If the mortality effect is correct, and if that mortality effect is related to early treatment, that would be transformative in terms of how we think about acute heart failure. It would mean that just as in myocardial infarction, where time is of the essence, it could be that in acute heart failure time is of the essence. So if the mortality effect is true, this trial changes the way we do things," said Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

It’s plausible that decompressing the heart quite early in an episode of acute heart failure, when the heart is being actively distended, reduces myocardial injury and thereby lowers cardiovascular risk long term. The drop in cardiac troponin levels seen with serelaxin therapy is consistent with such a scenario, according to Dr. Packer.

Dr. Gregg Fonarow said in an interview that on the strength of the evidence from RELAX-AHF plus the phase III study, including the absence of any safety concerns, he thinks serelaxin would readily earn Food and Drug Administration approval for the relief of signs and symptoms of acute heart failure. But winning an indication for mortality reduction might require a confirmatory trial.

"To have a drug that relieves symptoms and improves survival in patients hospitalized with acute heart failure would be off-the-charts exciting after 20 years of trial and error," added Dr. Fonarow, professor of medicine and director of the Ahmanson-UCLA Cardiomyopathy Center.

A spokesperson for Novartis, which sponsored RELAX-AHF, told this publication that the company hasn’t yet determined its filing strategy but believes "this is a strong set of data," and has begun discussions with the major regulatory agencies.

Simultaneous with Dr. Teerlink’s presentation, the RELAX-AHF findings were published online (Lancet 2012 Nov. 7 [doi: 10.1016/S0140-6736(12)61855-8]).

The trial was sponsored by Novartis. Dr. Teerlink reported that he has received research grants from and serves as a consultant to Novartis as well as other pharmaceutical and medical device companies. The discussants reported having no financial conflicts.

LOS ANGELES – The recombinant vasoactive peptide hormone serelaxin showed the potential to be a breakthrough therapy for acute heart failure in a phase III randomized trial.

In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin brought greater dyspnea relief than standard treatment plus placebo. It also markedly reduced the risk of worsening heart failure during the index hospitalization, significantly shortened ICU and total hospital lengths of stay, improved biomarkers, and displayed a benign safety profile. Most impressive of all, serelaxin was associated with a highly significant 37% reduction in both cardiovascular and all-cause mortality at follow-up 6 months after administration of a 48-hour infusion, study co-principal investigator Dr. John R. Teerlink reported on Nov. 6 at the annual scientific sessions of the American Heart Association.

These benefits mirror those seen earlier in the phase II Pre-RELAX-AHF study (Lancet 2009;373:1429-39). That study showed an all-cause mortality reduction in the subgroup randomized to the same dose of serelaxin used in the phase III trial, added Dr. Teerlink, professor of medicine at the University of California, San Francisco.

Serelaxin is recombinant human relaxin-2, which is present in both men and women. The hormone rises to pharmacologic levels during pregnancy. During that time, it promotes increased cardiac output, renal blood flow, and arterial compliance.

"Those are exactly the kinds of changes we’d like to see in patients with acute heart failure," Dr. Teerlink explained in describing the rationale for developing the hormone as a novel cardiovascular medication.

Heart failure experts who commented on RELAX-AHF were unanimous in their conviction that the study persuasively demonstrated that serelaxin reduces breathlessness and other signs and symptoms of acute heart failure. They were more cautious regarding the observed mortality benefit.

"My own feeling about this is that it would be very nice to see this finding replicated. If we did replicate this finding it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or lifesaving therapies," said Dr. John McMurray, professor of medical cardiology at the University of Glasgow.

RELAX-AHF was an international double-blind study that enrolled 1,161 patients hospitalized for acute heart failure. All had dyspnea at rest or with minimal exertion, pulmonary congestion, mild to moderate renal insufficiency, elevated brain natriuretic peptide levels, and a systolic blood pressure greater than 125 mm Hg despite having received at least 40 mg of intravenous furosemide or its equivalent shortly before enrollment. Participants were randomized to intravenous serelaxin at 30 mcg/kg per day for 48 hours or placebo on top of standard management.

The results: The serelaxin-treated group experienced a 19% improvement in the primary end point of patient-reported dyspnea to day 5. They also had a 30% reduction in the relative risk of worsening heart failure events up to day 14, despite roughly 25% less use of intravenous diuretics and other vasoactive drugs than in the placebo group. The average length of the initial hospital stay was 9.6 days in the serelaxin group, and nearly a full day longer at 10.5 days in controls. The serelaxin group averaged 3.5 days in the ICU or coronary care unit, 0.4 days less than the placebo group.

They were less likely than controls to experience a significant rise in creatinine or troponin T at day 2, and more likely to have a substantial decrease in NT-proBNP and liver enzymes.

But the head-turning result was the cardiovascular death rate through day 180: 9.5% with placebo compared with 6.0% with serelaxin, for a 37% reduction in risk. The number of patients who needed to be treated with serelaxin for 48 hours in order to prevent one additional cardiovascular death was 29. All-cause mortality was reduced to a similar extent, with an 11.3% rate in controls, compared with 7.3% with serelaxin.

Rates and types of adverse events overall and serious adverse events were similar in the two study arms.

But not all prespecified end points were met. Most important, in Dr. McMurray’s view, was the serelaxin group’s lack of a reduction in rehospitalizations for heart failure or renal failure during 60 days of follow-up. In chronic heart failure, it’s very unusual to see a treatment that improves survival but does not reduce rehospitalization. Also, 6-month mortality was not a prespecified end point in RELAX-AHF. And the mortality conclusions were based on relatively small numbers.

"In acute heart failure in the past, we’ve been famously misled by small numbers," he said, citing the example of vesnarinone, which in its first randomized trial showed a 62% reduction in all-cause mortality that didn’t hold up in a second, much larger trial.

Dr. Milton Packer drew attention to the impressively short time between hospital admission and the start of serelaxin, which averaged less than 8 hours.

"No trial has ever pulled that off before. And here’s the thing that’s really exciting about RELAX-AHF: If the mortality effect is correct, and if that mortality effect is related to early treatment, that would be transformative in terms of how we think about acute heart failure. It would mean that just as in myocardial infarction, where time is of the essence, it could be that in acute heart failure time is of the essence. So if the mortality effect is true, this trial changes the way we do things," said Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

It’s plausible that decompressing the heart quite early in an episode of acute heart failure, when the heart is being actively distended, reduces myocardial injury and thereby lowers cardiovascular risk long term. The drop in cardiac troponin levels seen with serelaxin therapy is consistent with such a scenario, according to Dr. Packer.

Dr. Gregg Fonarow said in an interview that on the strength of the evidence from RELAX-AHF plus the phase III study, including the absence of any safety concerns, he thinks serelaxin would readily earn Food and Drug Administration approval for the relief of signs and symptoms of acute heart failure. But winning an indication for mortality reduction might require a confirmatory trial.

"To have a drug that relieves symptoms and improves survival in patients hospitalized with acute heart failure would be off-the-charts exciting after 20 years of trial and error," added Dr. Fonarow, professor of medicine and director of the Ahmanson-UCLA Cardiomyopathy Center.

A spokesperson for Novartis, which sponsored RELAX-AHF, told this publication that the company hasn’t yet determined its filing strategy but believes "this is a strong set of data," and has begun discussions with the major regulatory agencies.

Simultaneous with Dr. Teerlink’s presentation, the RELAX-AHF findings were published online (Lancet 2012 Nov. 7 [doi: 10.1016/S0140-6736(12)61855-8]).

The trial was sponsored by Novartis. Dr. Teerlink reported that he has received research grants from and serves as a consultant to Novartis as well as other pharmaceutical and medical device companies. The discussants reported having no financial conflicts.

LOS ANGELES – The recombinant vasoactive peptide hormone serelaxin showed the potential to be a breakthrough therapy for acute heart failure in a phase III randomized trial.

In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin brought greater dyspnea relief than standard treatment plus placebo. It also markedly reduced the risk of worsening heart failure during the index hospitalization, significantly shortened ICU and total hospital lengths of stay, improved biomarkers, and displayed a benign safety profile. Most impressive of all, serelaxin was associated with a highly significant 37% reduction in both cardiovascular and all-cause mortality at follow-up 6 months after administration of a 48-hour infusion, study co-principal investigator Dr. John R. Teerlink reported on Nov. 6 at the annual scientific sessions of the American Heart Association.

These benefits mirror those seen earlier in the phase II Pre-RELAX-AHF study (Lancet 2009;373:1429-39). That study showed an all-cause mortality reduction in the subgroup randomized to the same dose of serelaxin used in the phase III trial, added Dr. Teerlink, professor of medicine at the University of California, San Francisco.

Serelaxin is recombinant human relaxin-2, which is present in both men and women. The hormone rises to pharmacologic levels during pregnancy. During that time, it promotes increased cardiac output, renal blood flow, and arterial compliance.

"Those are exactly the kinds of changes we’d like to see in patients with acute heart failure," Dr. Teerlink explained in describing the rationale for developing the hormone as a novel cardiovascular medication.

Heart failure experts who commented on RELAX-AHF were unanimous in their conviction that the study persuasively demonstrated that serelaxin reduces breathlessness and other signs and symptoms of acute heart failure. They were more cautious regarding the observed mortality benefit.

"My own feeling about this is that it would be very nice to see this finding replicated. If we did replicate this finding it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or lifesaving therapies," said Dr. John McMurray, professor of medical cardiology at the University of Glasgow.

RELAX-AHF was an international double-blind study that enrolled 1,161 patients hospitalized for acute heart failure. All had dyspnea at rest or with minimal exertion, pulmonary congestion, mild to moderate renal insufficiency, elevated brain natriuretic peptide levels, and a systolic blood pressure greater than 125 mm Hg despite having received at least 40 mg of intravenous furosemide or its equivalent shortly before enrollment. Participants were randomized to intravenous serelaxin at 30 mcg/kg per day for 48 hours or placebo on top of standard management.

The results: The serelaxin-treated group experienced a 19% improvement in the primary end point of patient-reported dyspnea to day 5. They also had a 30% reduction in the relative risk of worsening heart failure events up to day 14, despite roughly 25% less use of intravenous diuretics and other vasoactive drugs than in the placebo group. The average length of the initial hospital stay was 9.6 days in the serelaxin group, and nearly a full day longer at 10.5 days in controls. The serelaxin group averaged 3.5 days in the ICU or coronary care unit, 0.4 days less than the placebo group.

They were less likely than controls to experience a significant rise in creatinine or troponin T at day 2, and more likely to have a substantial decrease in NT-proBNP and liver enzymes.

But the head-turning result was the cardiovascular death rate through day 180: 9.5% with placebo compared with 6.0% with serelaxin, for a 37% reduction in risk. The number of patients who needed to be treated with serelaxin for 48 hours in order to prevent one additional cardiovascular death was 29. All-cause mortality was reduced to a similar extent, with an 11.3% rate in controls, compared with 7.3% with serelaxin.

Rates and types of adverse events overall and serious adverse events were similar in the two study arms.

But not all prespecified end points were met. Most important, in Dr. McMurray’s view, was the serelaxin group’s lack of a reduction in rehospitalizations for heart failure or renal failure during 60 days of follow-up. In chronic heart failure, it’s very unusual to see a treatment that improves survival but does not reduce rehospitalization. Also, 6-month mortality was not a prespecified end point in RELAX-AHF. And the mortality conclusions were based on relatively small numbers.

"In acute heart failure in the past, we’ve been famously misled by small numbers," he said, citing the example of vesnarinone, which in its first randomized trial showed a 62% reduction in all-cause mortality that didn’t hold up in a second, much larger trial.

Dr. Milton Packer drew attention to the impressively short time between hospital admission and the start of serelaxin, which averaged less than 8 hours.

"No trial has ever pulled that off before. And here’s the thing that’s really exciting about RELAX-AHF: If the mortality effect is correct, and if that mortality effect is related to early treatment, that would be transformative in terms of how we think about acute heart failure. It would mean that just as in myocardial infarction, where time is of the essence, it could be that in acute heart failure time is of the essence. So if the mortality effect is true, this trial changes the way we do things," said Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

It’s plausible that decompressing the heart quite early in an episode of acute heart failure, when the heart is being actively distended, reduces myocardial injury and thereby lowers cardiovascular risk long term. The drop in cardiac troponin levels seen with serelaxin therapy is consistent with such a scenario, according to Dr. Packer.

Dr. Gregg Fonarow said in an interview that on the strength of the evidence from RELAX-AHF plus the phase III study, including the absence of any safety concerns, he thinks serelaxin would readily earn Food and Drug Administration approval for the relief of signs and symptoms of acute heart failure. But winning an indication for mortality reduction might require a confirmatory trial.

"To have a drug that relieves symptoms and improves survival in patients hospitalized with acute heart failure would be off-the-charts exciting after 20 years of trial and error," added Dr. Fonarow, professor of medicine and director of the Ahmanson-UCLA Cardiomyopathy Center.

A spokesperson for Novartis, which sponsored RELAX-AHF, told this publication that the company hasn’t yet determined its filing strategy but believes "this is a strong set of data," and has begun discussions with the major regulatory agencies.

Simultaneous with Dr. Teerlink’s presentation, the RELAX-AHF findings were published online (Lancet 2012 Nov. 7 [doi: 10.1016/S0140-6736(12)61855-8]).

The trial was sponsored by Novartis. Dr. Teerlink reported that he has received research grants from and serves as a consultant to Novartis as well as other pharmaceutical and medical device companies. The discussants reported having no financial conflicts.