- Email: [email protected]
Occlusion of left atrial appendage to treat atrial fibrillation
Correspondence
Tight-control group
at 1-year and 2-year follow-up, respectively. Hence, the potential drug combinations were so many to preclude any meaningful comparison. Furthermore, since the therapeutic management was tailored to every patient’s need at each visit without any forced scheme, it was unfeasible to control for all episodes of uptitration or downtitration of treatment. Finally, since the readers of electrocardiographic tracings were unaware of the randomisation code, the potential bias introduced by the open design did not extend to the assessment of LVH, the primary endpoint of the study. Jonas Green and Adam Richards raise an apparent inconsistency with our previous publication with regard to the policy of downtitration of therapy in patients allocated to the usual control group and systolic blood pressure below 130 mm Hg. Once again, we remake the point that treatment could be either left unchanged or downtitrated, by protocol, at the total discretion and responsibility of the field investigator. This choice has been made not to contradict the guidelines, but to mimic as much as possible doctors’ choices in everyday practice. We do not share the interpretation that such a policy led to a substantial underestimation of the potentially achievable blood pressure control in the usual-control group. A few numbers were misquoted in our printed article. The correct numbers of patients who achieved the target blood pressure in the two groups are shown in the table and were corrected in an erratum in the Sept 12 issue. Overall, the degree of blood pressure control was good. For comparison, a large survey in Italy reported a rate of systolic blood pressure control (<140 mm Hg) of 24% in treated hypertensive patients.5
<140 mm Hg
66·9% (334/499)
76·5% (388/507)
We declare that we have no conflicts of interest.
<130 mm Hg
27·3% (136/499)
45·4% (230/507)
*Paolo Verdecchia, Fabio Angeli, Jan A Staessen, Gianpaolo Reboldi
3
4
Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–87. Cardio-Sis Study Group. Randomized study of traditional versus aggressive systolic blood pressure control (Cardio-Sis): rationale, design and characteristics of the study population. J Hum Hypertens 2008; 22: 243–51.
Authors’ reply
See Department of Error Lancet 2009; 374: 880
Saurabh Rai and colleagues suggest that imbalances in drug treatment between the two groups may partly explain the different pattern of left-ventricular hypertrophy (LVH). However, this possibility is unlikely for several reasons. First, the number of antihypertensive drug classes patients were taking increased from baseline in both study groups (p<0·0001) without any statistical differences between the two groups (p=0·79). Second, when individual drug classes were examined separately, diuretics were given more frequently in the tight-control group than in the usual-control group (odds ratio 1·36, 95% CI 1·08–1·71; p=0·009). Diuretics are believed to be less effective than other drug classes for achieving regression of LVH.1 Contrary to Rai and colleagues’ interpretation, we found no statistical evidence of a more frequent use of angiotensin-receptor blockers (ARBs) in the tight-control group (p=0·07). Rai and colleagues’ argument that combination therapy induces regression of LVH “more quickly and completely than single agents” is poorly supported. They cite a small study in 24 patients,2 a review article,3 and a meta-analysis.4 In the context of our study, it was impractical to compare various antihypertensive combinations because, on average, 2·8 and 2·9 drug classes were used
Usual-control group
Table: Achieved systolic blood pressure at 2-year follow-up in the two study groups
1742
[email protected]
Division of Cardiology, Hospital S Maria della Misericordia, 06100 Perugia, Italy (PV, FA); Division of Hypertension and Cardiac Rehabilitation, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium (JAS); and Department of Internal Medicine, University of Perugia, Perugia, Italy (GR) 1
2
3
4
5
Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003; 115: 41–46. Grandi AM, Solbiati F, Laurita E, et al. Effects of dual blockade of renin-angiotensin system on concentric left ventricular hypertrophy in essential hypertension: a randomized, controlled pilot study. Am J Hypertens 2008; 21: 231–37. Devereux RB. Therapeutic options in minimizing left ventricular hypertrophy. Am Heart J 2000; 139: S9–14. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA 1996; 275: 1507–13. Volpe M, Tocci G, Trimarco B, et al. Blood pressure control in Italy: results of recent surveys on hypertension. J Hypertens 2007; 25: 1491–98.
Occlusion of left atrial appendage to treat atrial fibrillation We congratulate David Holmes and colleagues on the landmark PROTECT AF trial (Aug 15, p 345).1 This study shows, via statistical modelling, that a new strategy— occlusion of the left atrial appendage (LAA) with the WATCHMAN device— is non-inferior to warfarin in patients with atrial fibrillation. Does this result mean a “new dawn” in management of these patients? Well perhaps, but if this device is to have a future, we need to understand the complications better so we can reduce them. The paper describes an increased rate of pericardial effusions in the intervention group. Were these related to trans-septal puncture? The LAA is a very delicate and thin-walled structure and even injection of radioopaque contrast through a catheter, if abutting the wall, can be enough to result in perforation. We recommend injecting contrast through a multiholed pigtail catheter which can be passed through the trans-septal sheath. A further potential origin of www.thelancet.com Vol 374 November 21, 2009
Correspondence
LAA trauma may relate to the fixation barbs. Too enthusiastic a tug on the device during stability testing may result in a pericardial effusion requiring intervention. The paper reports that five of 408 patients who had a device implanted had periprocedural strokes, and this was attributed by Holmes and colleagues to be “mainly air embolism”. Air embolisation can generally be overcome with studious attention to de-airing of catheters and devices. Now that percutaneous coronary intervention has already passed its zenith, it may be tempting for coronary interventionalists to turn their hands to this procedure. However, the complication rates of the PROTECT AF study herald a warning against this. We recommend that the procedure only be adopted by operators experienced at structural intervention in the left atrium (in particular atrial septal closure). We declare that we have no conflicts of interest.
*Patrick A Calvert, Bushra S Rana, David A Begley, Leonard M Shapiro [email protected] Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK (PAC, BSR, DB, LMS); and Cambridge University, Cambridge, UK (PAC) 1
Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374: 534–42.
Author’s reply We appreciate the comments from Patrick Calvert and colleagues. They are extremely relevant and important to the field. Any invasive procedure has certain risks. In the case of our trial of this technology, pericardial effusions were the most common serious adverse event. Although they did not cause death, they did prolong hospital stay and often required treatment, either percutaneously or even surgically. Some baseline frequency of pericardial effusion has been documented with essentially all intracardiac procedures, www.thelancet.com Vol 374 November 21, 2009
both interventional cardiology and electrophysiological and pacing procedures. It is sometimes difficult to ascertain the specific cause of pericardial effusion, which could be related in this case to either the trans-septal procedure, access to the left atrial appendage, or the specifics of device placement. Calvert and colleagues mention the importance of “injecting contrast through a multiholed pigtail catheter”. This was implemented during the course of the PROTECT AF study. Additionally, operator experience improved and the technology continued to evolve. In the Continued Access Registry with the WATCHMAN device, the pericardial effusion rate is now down to 2–3% in about 200 patients (unpublished data). This is similar to reports of other interventions such as atrial fibrillation ablation. Intense efforts are underway to further reduce this. In terms of periprocedural strokes, which were often related to air embolism, the issues that Calvert and colleagues mention are exceedingly important and, with meticulous attention to detail, can be minimised. Indeed, in the Continued Access Registry, periprocedural strokes have been eliminated. Clearly the risk–benefit ratio of every therapeutic strategy needs to be carefully considered. Interventional procedures do indeed need to be carried out by “operators experienced at structural intervention in the left atrium”. Careful selection of patients, meticulous attention to detail, and superb technical expertise and experience are all mandatory to bring this “new dawn” forward. Both Mayo Clinic and DRH have a financial interest in technology related to this research. That technology has been licensed to Atritech, and Mayo Clinic and DRH have contractual rights to receive future royalties from this licence. To date, no royalties have been received by either Mayo Clinic or DRH.
David R Holmes [email protected] Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Insulin glargine and cancer Stuart Pocock and Liam Smeeth (Aug 15, p 511)1 criticise our study2 because allocation to treatment groups and drug dose was not determined before follow-up, but treatment and dose cannot be determined prospectively in registry studies. Real-life treatment decisions are made by doctors and patients, and not according to a protocol, as in randomised controlled trials. We showed that the risk of cancer diagnosis increased with the dose of insulin. This important factor is essential because of its biological effects, and it must be corrected for in the primary analysis. Similar use of follow-up information and adjustments are frequently applied in epidemiological practice (for example the British Doctors’ Study3 used follow-up data to define the group of lifelong non-smokers). We agree that such analyses should be interpreted with great caution, but they are neither “fundamentally flawed” nor “uninterpretable”. Pocock and colleagues have themselves suggested this to account for nonrandomised therapeutic interventions during follow-up in pragmatic trials.4 Pocock and Smeeth argue that removing patients who used other insulins in addition to glargine might have resulted in differences between groups. We agree, but this is likely to have resulted in an exclusion of sicker patients from the glargine group. The glargine group was in fact “healthier” than the human insulin group, which could lead to a possible underestimation of the effect on cancer risk. Patients need confidence in drugs they inject themselves with daily. We believe that the burden of proof lies with the manufacturer when it comes to drug safety. Pocock and Smeeth claim that the three registry studies have raised an “unwarranted alarm”. We disagree. In-vitro data suggested 1743
Tight-control group
at 1-year and 2-year follow-up, respectively. Hence, the potential drug combinations were so many to preclude any meaningful comparison. Furthermore, since the therapeutic management was tailored to every patient’s need at each visit without any forced scheme, it was unfeasible to control for all episodes of uptitration or downtitration of treatment. Finally, since the readers of electrocardiographic tracings were unaware of the randomisation code, the potential bias introduced by the open design did not extend to the assessment of LVH, the primary endpoint of the study. Jonas Green and Adam Richards raise an apparent inconsistency with our previous publication with regard to the policy of downtitration of therapy in patients allocated to the usual control group and systolic blood pressure below 130 mm Hg. Once again, we remake the point that treatment could be either left unchanged or downtitrated, by protocol, at the total discretion and responsibility of the field investigator. This choice has been made not to contradict the guidelines, but to mimic as much as possible doctors’ choices in everyday practice. We do not share the interpretation that such a policy led to a substantial underestimation of the potentially achievable blood pressure control in the usual-control group. A few numbers were misquoted in our printed article. The correct numbers of patients who achieved the target blood pressure in the two groups are shown in the table and were corrected in an erratum in the Sept 12 issue. Overall, the degree of blood pressure control was good. For comparison, a large survey in Italy reported a rate of systolic blood pressure control (<140 mm Hg) of 24% in treated hypertensive patients.5
<140 mm Hg
66·9% (334/499)
76·5% (388/507)
We declare that we have no conflicts of interest.
<130 mm Hg
27·3% (136/499)
45·4% (230/507)
*Paolo Verdecchia, Fabio Angeli, Jan A Staessen, Gianpaolo Reboldi
3
4
Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–87. Cardio-Sis Study Group. Randomized study of traditional versus aggressive systolic blood pressure control (Cardio-Sis): rationale, design and characteristics of the study population. J Hum Hypertens 2008; 22: 243–51.
Authors’ reply
See Department of Error Lancet 2009; 374: 880
Saurabh Rai and colleagues suggest that imbalances in drug treatment between the two groups may partly explain the different pattern of left-ventricular hypertrophy (LVH). However, this possibility is unlikely for several reasons. First, the number of antihypertensive drug classes patients were taking increased from baseline in both study groups (p<0·0001) without any statistical differences between the two groups (p=0·79). Second, when individual drug classes were examined separately, diuretics were given more frequently in the tight-control group than in the usual-control group (odds ratio 1·36, 95% CI 1·08–1·71; p=0·009). Diuretics are believed to be less effective than other drug classes for achieving regression of LVH.1 Contrary to Rai and colleagues’ interpretation, we found no statistical evidence of a more frequent use of angiotensin-receptor blockers (ARBs) in the tight-control group (p=0·07). Rai and colleagues’ argument that combination therapy induces regression of LVH “more quickly and completely than single agents” is poorly supported. They cite a small study in 24 patients,2 a review article,3 and a meta-analysis.4 In the context of our study, it was impractical to compare various antihypertensive combinations because, on average, 2·8 and 2·9 drug classes were used
Usual-control group
Table: Achieved systolic blood pressure at 2-year follow-up in the two study groups
1742
[email protected]
Division of Cardiology, Hospital S Maria della Misericordia, 06100 Perugia, Italy (PV, FA); Division of Hypertension and Cardiac Rehabilitation, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium (JAS); and Department of Internal Medicine, University of Perugia, Perugia, Italy (GR) 1
2
3
4
5
Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003; 115: 41–46. Grandi AM, Solbiati F, Laurita E, et al. Effects of dual blockade of renin-angiotensin system on concentric left ventricular hypertrophy in essential hypertension: a randomized, controlled pilot study. Am J Hypertens 2008; 21: 231–37. Devereux RB. Therapeutic options in minimizing left ventricular hypertrophy. Am Heart J 2000; 139: S9–14. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA 1996; 275: 1507–13. Volpe M, Tocci G, Trimarco B, et al. Blood pressure control in Italy: results of recent surveys on hypertension. J Hypertens 2007; 25: 1491–98.
Occlusion of left atrial appendage to treat atrial fibrillation We congratulate David Holmes and colleagues on the landmark PROTECT AF trial (Aug 15, p 345).1 This study shows, via statistical modelling, that a new strategy— occlusion of the left atrial appendage (LAA) with the WATCHMAN device— is non-inferior to warfarin in patients with atrial fibrillation. Does this result mean a “new dawn” in management of these patients? Well perhaps, but if this device is to have a future, we need to understand the complications better so we can reduce them. The paper describes an increased rate of pericardial effusions in the intervention group. Were these related to trans-septal puncture? The LAA is a very delicate and thin-walled structure and even injection of radioopaque contrast through a catheter, if abutting the wall, can be enough to result in perforation. We recommend injecting contrast through a multiholed pigtail catheter which can be passed through the trans-septal sheath. A further potential origin of www.thelancet.com Vol 374 November 21, 2009
Correspondence
LAA trauma may relate to the fixation barbs. Too enthusiastic a tug on the device during stability testing may result in a pericardial effusion requiring intervention. The paper reports that five of 408 patients who had a device implanted had periprocedural strokes, and this was attributed by Holmes and colleagues to be “mainly air embolism”. Air embolisation can generally be overcome with studious attention to de-airing of catheters and devices. Now that percutaneous coronary intervention has already passed its zenith, it may be tempting for coronary interventionalists to turn their hands to this procedure. However, the complication rates of the PROTECT AF study herald a warning against this. We recommend that the procedure only be adopted by operators experienced at structural intervention in the left atrium (in particular atrial septal closure). We declare that we have no conflicts of interest.
*Patrick A Calvert, Bushra S Rana, David A Begley, Leonard M Shapiro [email protected] Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK (PAC, BSR, DB, LMS); and Cambridge University, Cambridge, UK (PAC) 1
Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374: 534–42.
Author’s reply We appreciate the comments from Patrick Calvert and colleagues. They are extremely relevant and important to the field. Any invasive procedure has certain risks. In the case of our trial of this technology, pericardial effusions were the most common serious adverse event. Although they did not cause death, they did prolong hospital stay and often required treatment, either percutaneously or even surgically. Some baseline frequency of pericardial effusion has been documented with essentially all intracardiac procedures, www.thelancet.com Vol 374 November 21, 2009
both interventional cardiology and electrophysiological and pacing procedures. It is sometimes difficult to ascertain the specific cause of pericardial effusion, which could be related in this case to either the trans-septal procedure, access to the left atrial appendage, or the specifics of device placement. Calvert and colleagues mention the importance of “injecting contrast through a multiholed pigtail catheter”. This was implemented during the course of the PROTECT AF study. Additionally, operator experience improved and the technology continued to evolve. In the Continued Access Registry with the WATCHMAN device, the pericardial effusion rate is now down to 2–3% in about 200 patients (unpublished data). This is similar to reports of other interventions such as atrial fibrillation ablation. Intense efforts are underway to further reduce this. In terms of periprocedural strokes, which were often related to air embolism, the issues that Calvert and colleagues mention are exceedingly important and, with meticulous attention to detail, can be minimised. Indeed, in the Continued Access Registry, periprocedural strokes have been eliminated. Clearly the risk–benefit ratio of every therapeutic strategy needs to be carefully considered. Interventional procedures do indeed need to be carried out by “operators experienced at structural intervention in the left atrium”. Careful selection of patients, meticulous attention to detail, and superb technical expertise and experience are all mandatory to bring this “new dawn” forward. Both Mayo Clinic and DRH have a financial interest in technology related to this research. That technology has been licensed to Atritech, and Mayo Clinic and DRH have contractual rights to receive future royalties from this licence. To date, no royalties have been received by either Mayo Clinic or DRH.
David R Holmes [email protected] Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Insulin glargine and cancer Stuart Pocock and Liam Smeeth (Aug 15, p 511)1 criticise our study2 because allocation to treatment groups and drug dose was not determined before follow-up, but treatment and dose cannot be determined prospectively in registry studies. Real-life treatment decisions are made by doctors and patients, and not according to a protocol, as in randomised controlled trials. We showed that the risk of cancer diagnosis increased with the dose of insulin. This important factor is essential because of its biological effects, and it must be corrected for in the primary analysis. Similar use of follow-up information and adjustments are frequently applied in epidemiological practice (for example the British Doctors’ Study3 used follow-up data to define the group of lifelong non-smokers). We agree that such analyses should be interpreted with great caution, but they are neither “fundamentally flawed” nor “uninterpretable”. Pocock and colleagues have themselves suggested this to account for nonrandomised therapeutic interventions during follow-up in pragmatic trials.4 Pocock and Smeeth argue that removing patients who used other insulins in addition to glargine might have resulted in differences between groups. We agree, but this is likely to have resulted in an exclusion of sicker patients from the glargine group. The glargine group was in fact “healthier” than the human insulin group, which could lead to a possible underestimation of the effect on cancer risk. Patients need confidence in drugs they inject themselves with daily. We believe that the burden of proof lies with the manufacturer when it comes to drug safety. Pocock and Smeeth claim that the three registry studies have raised an “unwarranted alarm”. We disagree. In-vitro data suggested 1743