Year in Review: Physicians Highlight the Most Important Interventional News of 2013
From ‘complete revascularization’ for patients with ST-segment elevation myocardial infarction (STEMI) to percutaneous revascularization for renal artery stenosis, the past year has seen numerous important developments in the field of interventional cardiology. TCTMD asked several prominent interventionalists to share their views on the most significant events of 2013.
Our physician panel referenced several seminal trials from the past year including PRAMI, CORAL, and SAFE-PCI. Another landmark event was the decision made by the US Food and Drug Administration (FDA) to approve the MitraClip device for treatment of patients with significant symptomatic degenerative mitral regurgitation who are at prohibitive risk for surgery
PRAMI
Full results of the PRAMI trial were presented by David S. Wald, MD, of the Wolfson Institute of Preventive Medicine, Barts, and the London School of Medicine and Dentistry (London, United Kingdom), on September 1, 2013, at the European Society of Cardiology Congress in Amsterdam, The Netherlands, and simultaneously published online ahead of print in the New England Journal of Medicine.
Compared with infarct-only revascularization in patients with acute STEMI undergoing PCI, PRAMI (Preventive Angioplasty in Acute Myocardial Infarction) showed that complete revascularization, or ‘preventative’ PCI, reduces the risk of cardiovascular events by two-thirds.
Dr. Wald and colleagues planned to enroll 600 STEMI patients with multivessel disease and randomly assign them to PCI in the infarct-related artery with or without immediate treatment of other stenosed vessels. All other aspects of patient management were at physician discretion, and subsequent PCI was reserved only for patients with documented refractory angina. However, the study was stopped early when interim results showed a “clear” advantage for the preventive strategy after only 465 patients were treated, Dr. Wald reported.
Over a mean follow-up period of 23 months, the combined rate of cardiac death, nonfatal MI, and refractory angina (primary endpoint) was 9% in patients who received complete revascularization (n = 234) and 23% in those who had infarct-only PCI (n = 231). Nonfatal MI and refractory angina each were lower with the preventive strategy, as was the secondary outcome of repeat revascularization.
Procedure time, fluoroscopy dose, and contrast volume all were higher when patients underwent PCI in all diseased arteries, though complication rates were similar between the 2 groups (P = 0.86).
Commentary
Hitinder S. Gurm, MD
University of Michigan Cardiovascular Center
Ann Arbor, MI
PRAMI challenged the existing dogma that non-culprit lesions should be not touched during primary PCI and proved that the conventional wisdom was incorrect. This trial clearly established the benefits of non-culprit lesion PCI, although the optimal timing for this is debatable. My belief is that the common practice of waiting for a day or 2 after primary PCI is preferable, but at the same time, complete revascularization in the primary setting should no longer be considered inappropriate.
Morton J. Kern, MD
University of California, Irvine
Irvine, CA
The finding that the complete or preventive arm had lower death and MACE than the culprit-only arm was counter to the 3 prior major studies that supported the 2011 PCI guideline class III recommendation for stenting more than the culprit-only vessel. Criticisms of the PRAMI study included early cessation with small sample size, treatment of low risk STEMI patients, and no QCA or FFR of the non-infarct arteries that were stented.
The bottom line is that this is one of the most provocative and potentially important studies that may lead to a change in the way STEMI interventions will be performed in the future.
CORAL
The CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial, presented November 18, 2013, at the annual American Heart Association Scientific Sessions in Dallas, TX, and simultaneously published in the New England Journal of Medicine, examined the benefits of percutaneous revascularization for renal artery stenosis (RAS).
Researchers looked at 947 RAS patients with either systolic hypertension while taking 2 or more antihypertensive drugs or chronic kidney disease. Patients were randomized to medical therapy with (n = 459) or without (n = 472) stenting. Medical therapy consisted of candesartan with or without hydrochlorothiazide and the combination agent amlodipine-atorvastatin. The Palmaz Genesis stent (Cordis, Miami, FL) was used in the stenting group.
After a median follow-up of 43 months, there was no difference between groups in the primary composite endpoint of death from cardiovascular or renal causes, stroke, MI, hospitalization for CHF, progressive renal insufficiency, or permanent renal replacement therapy. Nor were there any differences in the individual component endpoints.
While systolic BP was lowered in both the stenting plus medical therapy group and the medical therapy alone group, it was modestly lower over the course of follow-up in the stent group (-2.3 mm Hg; 95% CI -4.4 to -0.2 mm Hg; P = 0.03). However, this reduction did not translate into any lowering of clinical events.
The primary and component endpoints remained unchanged by treatment modality across multiple subgroups defined by sex, race, presence of diabetes, or presence of global ischemia.
Commentary
Hitinder S. Gurm, MD
University of Michigan Medical Center
Ann Arbor, MI
The CORAL trial convincingly demonstrates that there is little role for routine revascularization for the management of atherosclerotic renal arterial disease. The challenge remains, however, in identifying patients who do benefit from renal stenting. Most of us recognize that the majority of patients do not demonstrate sustained improvement in renal function or blood pressure control after renal stenting, but in a small number, the procedure is associated with a dramatic clinical response. Until we can identify who those patients are, medical therapy should remain the preferred approach for patients with renal artery stenosis.
Christopher J. White, MD
Ochsner Heart and Vascular Institute
New Orleans, LA
The authors reasonably concluded multifactorial medical therapy to be the initial treatment of choice for patients with uncontrolled hypertension on 2 or more medications rather than renal stenting. The limitation of the CORAL trial is that the average renal artery stenosis treated was only 67%, once again making it very likely that non-obstructive or mild renal artery lesions were randomized. The study did not use hemodynamic gradients to confirm the severity of the lesions, which was a major flaw. Future trials, with hemodynamic confirmation of lesion severity, in patients who have failed anti-hypertensive medical therapy need to be conducted to resolve the question of the appropriate use of renal stenting.
SAFE-PCI
Looking at women only, the SAFE-PCI trial demonstrated the benefits of an initial strategy of radial artery access during cardiac catheterization or PCI. Investigators randomized 1,787 women at 60 US sites who were undergoing elective PCI, urgent PCI, or diagnostic catheterization with possible PCI to a radial or femoral approach.
Results, presented October 29, 2013, at the Transcatheter Cardiovascular Therapeutics symposium in San Francisco, CA, showed a nonsignificant reduction in bleeding or vascular complications with radial access in those who underwent PCI (P = 0.12) and a significant reduction in the overall population (P = 0.03).
Procedure duration, total radiation dose, and 30-day MACE were similar between the groups. There was, however, less contrast volume reported for radial access (–13 mL per PCI case).
In addition, radial access was the preferred approach by the majority of women undergoing PCI.
The trial did not reach its planned enrollment due to early termination. After 1,120 patients were randomized, review by the Data and Safety Monitoring Board showed that the primary efficacy event rate was markedly lower than expected. Though termination of the trial was recommended, no harm was noted in either arm and the steering committee voted to continue the study until enrollment in a quality-of-life substudy was complete.
Commentary
Morton J. Kern, MD
University of California, Irvine
Irvine, CA
The study was stopped early due to futility in the ability to reach the prespecified endpoints. This occurred mainly because of the lower than expected femoral complication rate predicted from prior studies and the mixing of both diagnostic and interventional procedures. Nonetheless, the advantage of the radial approach with reduced bleeding is always clinically important and strongly applies to women undergoing cardiac catheterization. The critics would add that the crossover rate from radial to femoral cath is higher than vice versa, but this is less of a problem than the higher rate of vascular complications, which have led to high morbidity and mortality in all other studies of this type.
PROTECT AF
Four-year results of the PROTECT AF trial were presented May 9, 2013, at the Heart Rhythm Society 34th Annual Scientific Sessions in Denver, CO. In agreement with previously presented findings, the study continues to show superiority of percutaneous left atrial appendage (LAA) closure with the Watchman device (Boston Scientific, Natick, MA) vs. warfarin.
The primary efficacy event (stroke, systemic embolism, and cardiovascular or unexplained death) rate per 100 patient-years was lower with the Watchman device compared with controls (2.3% vs. 3.8%), demonstrating a 40% relative risk reduction (RR 0.60; 95% CI 0.41-1.05). Subgroup analysis maintained these results but showed slight differences based on gender, CHADS2 score, and A-fib pattern. Notably, efficacy was not diminished among patients with a history of TIA/stroke.
In addition, in an intention-to-treat analysis, patients who received the novel device were at reduced risk compared with warfarin-treated patients for both all-cause mortality (3.2% vs. 4.8%; HR 0.66; 95% CI 0.45-0.98; P = 0.0379) and cardiovascular mortality (1.0% vs. 2.4%; HR 0.40; 95% CI 0.23-0.82; P = 0.0045). Causes of death were balanced between the study arms, but those treated with warfarin were more likely to die from hemorrhagic stroke (2.9% vs. 0.4%; P = 0.0098).
Although warfarin-treated patients initially had a clear advantage with regard to the primary safety endpoint (procedure-related events and major bleeding), by 4 years the difference in the number of events had equalized between the groups (RR of 1.17; 95% CI 0.78-1.95 for Watchman vs. warfarin).
Commentary
Ted Feldman, MD
Evanston Hospital
Evanston, IL
The Watchman device compared with warfarin, was found to diminish [rates of?] stroke, hemorrhagic stroke, and both total and cardiovascular mortality. These findings were in a relatively low risk group of atrial fibrillation patients with two-thirds of the population having CHADS2 risk scores of 1 or 2. In conjunction with the presentation of data from PREVAIL, a safety trial in which the safety endpoints were met, both the efficacy and safety of Watchman have been demonstrated.
MitraClip Approval
In October, the US Food and Drug Administration (FDA) approved MitraClip (Abbott Vascular, Santa Clara, CA), a catheter-delivered device, for treatment of patients with significant symptomatic degenerative mitral regurgitation who are at prohibitive risk for surgery.
The MitraClip system involves a clip that is inserted into the mitral valve via percutaneous femoral venous transseptal access. The device is then aligned above the valve in order to secure the mitral leaflets, creating a bridge that supports durability of repair and may limit dilatation of the annulus.
The approval came in the wake of a narrow FDA advisory committee decision made in March that the benefits of the device outweigh its risks in this patient group. Although the panel was nearly unanimous in support of MitraClip’s safety, a vote on efficacy went against the device by a 5 to 4 margin.
Commentary
Ted Feldman, MD
Evanston Hospital
Evanston, IL
Percutaneous mitral therapy was advanced greatly with the FDA approval of MitraClip for patients at high-risk for surgery with degenerative mitral regurgitation. At the same time, a change in the definition of high-surgical risk for the ongoing COAPT randomized trial also represents an important development. COAPT is assessing the impact of MitraClip in a functional mitral regurgitation heart failure population, utilizing the primary endpoint of repeat heart failure hospitalizations during the first year after therapy. Previously, the high-risk definition included an STS risk calculator score of 8% or greater. The definition was recently changed to an estimation of high risk for surgery by the site heart team in the trial. This definition is “real world” and encompasses the population of high-risk patients with severe mitral regurgitation who do not have any other therapeutic option.
Renal Sympathetic Denervation in Mild Resistant Hypertension
Catheter-based renal denervation for patients with moderate treatment-resistant hypertension has been further explored in 2013, building off of results from the Symplicity trial. Results of a small pilot study, published online July 10, 2013, ahead of print in the Journal of the American College of Cardiology, suggest an expanded role for the innovative therapy, which has shown efficacy against severe drug-resistant hypertension in multiple trials.
The findings were first presented at the American College of Cardiology (ACC)/i2 Scientific Session in San Francisco, CA, in March 2013.
For the prospective, multicenter trial, investigators performed renal denervation in 54 patients with a mean office BP of 151/83 mm Hg at baseline. Patients were treated with an average of 5.1 ± 1.4 antihypertensive drugs, although 3 individuals were not receiving a diuretic due to contraindications or intolerance. Baseline 24-hour ambulatory BP monitoring demonstrated readings of 130/80 mm Hg or higher. Radiofrequency ablation was delivered via the Symplicity Catheter System (Medtronic, Mountain View, CA).
At 6 months, BP was reduced by a mean 13/7 mm Hg, with mean systolic pressure declining to 138 ± 21 mm Hg and diastolic pressure to 75 ± 11 mm Hg (P < 0.001 for both changes). Office BP was considered controlled (< 140/90 mm Hg) in slightly more than half of patients (51%), while 61% experienced a ‘treatment response,’ defined as a systolic reduction of 10 mm Hg or more.
In the subgroup of 36 patients who had ambulatory BP monitoring both before and after denervation, 6-month ambulatory BP was decreased by 14/7 mm Hg (P < 0.001 for both systolic and diastolic reductions).
In addition, heart rate was reduced by 4 beats per minute (from 67 ± 11 to 63 ± 10; P = 0.006). The change in heart rate did not correlate with the reduction in systolic BP, suggesting that the heart rate change is independent of the intervention’s BP lowering effects.
Despite protocol recommendation to the contrary, 37% of patients curtailed their antihypertensive regimen during 6-month follow-up. Interestingly, in an exploratory analysis, reductions in systolic pressure (13 mm Hg) were identical between those who did and did not maintain their original regimen, while the decline in diastolic pressure was actually larger in patients who altered their medications (9 mm Hg vs. 6 mm Hg).
Commentary
Robert S. Schwartz, MD
Minneapolis Heart Institute Foundation
Minneapolis, MN
Renal denervation for resistant hypertension has taken the interventional cardiology community by storm. It is clear that if a device-based treatment can be proven effective in not only resistant hypertension, but also in non-resistant hypertension, then millions of patients stand to benefit. As with other therapies, the modality started out with a huge degree of interest for its success. However, as data from more clinical trials emerge it is clear that it is not a perfect solution.
This has given rise to skepticism on the part of some regarding the technology’s widespread application. Several factors are emerging in hypertension treatment with renal denervation. It is clearly safe at this point in time, unaccompanied by any short-term negative consequences. It is also clear that few clinical trials have shown any deterioration of renal function. However, about 20% of patients will have renal artery anatomy that is not suitable for catheter-based ablation.
It is clear that many of the long-term effects are permanent in terms of blood pressure reduction. However, nonresponders become an issue and the question at the same time. Questions have been raised regarding whether sympathetic nerves regenerate, although this does not appear to occur out to at least 3 years, demonstrated by the Symplicity data.
The focus then turns to causes for nonresponse. Several clinically relevant issues including the number of ablations per artery, as well as heart rate change did not predict long-term blood pressure response.
Another key question is whether alternative energies or chemo ablation will be successful. Early data suggest that they in fact will be useful.
Other important questions arise about the ideal method for measurement and whether ambulatory blood pressure readings are necessary or whether office base blood pressure will suffice. Data will be forthcoming on this point shortly.
Migration of the technology "downward" into the moderate hypertensive population will be answered as the Symplicity IV trial will begin shortly with such patients.
In summary, many questions arise regarding types of energy, patients to treat, reasons for treatment resistance and methods of measurement. 2013 is a seminal year as these questions begin to emerge and additional questions will be tackled as they in turn are answered.
TAVR Developments
As transcathether aortic valve replacement (TAVR) becomes more widespread, research has been published regarding moderate-risk patients and also bleeding risk with TAVR compared with surgery. Second-generation devices are also being investigated with promising outcomes.
Commentary
Ted Feldman, MD
Evanston Hospital
Evanston, IL
The approval of TAVR and the sequence of trials leading to FDA labeling for use in patients considered inoperable, and then further expanded to high-risk operable patients, reflects the application of trial data to labeled indications for therapy. An important development in 2013 was the expansion of labeling for TAVR to alternative access routes based on the TVT Registry of the National Cardiovascular Data Registry (NCDR). Collection of clinical practice post market data for TAVR is mandated by the Centers for Medicare and Medicaid National Coverage Decision, and the aggregate of these data were used to expand indications to include alternative access sites beyond transfemoral and transapical. This is an important landmark in the utilization of registry data to fill in the gaps that are typical from randomized trials.
Another important development in the TAVR field is the emergence of next-generation devices into approved use in Europe and recognition that these devices will incrementally solve some of the problems seen with first-generation TAVR devices. Several platforms including the Direct Flow Medical valve, the Boston Scientific Lotus valve, and the Edwards SAPIEN 3 address the challenge of perivalvular leak. These devices all have a specific mechanism to minimize significant perivalvular leak.
Sources:
1. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;Epub ahead of print.
2. Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013;Epub ahead of print.
3. Rao SV. SAFE PCI for Women. Presented at: Transcatheter Cardiovascular Therapeutics; October 29, 2013; San Francisco, CA.
4. Reddy VY. Long term results of PROTECT AF: The mortality effects of left atrial appendage closure versus warfarin for stroke prophylaxis in AF. Presented at: Heart Rhythm Society 34th Annual Scientific Sessions; May 9, 2013; Denver, CO.
5. Abbott Vascular. Abbott’s first-in-class MitraClip device now available for US patients [press release]. http://www.abbott.com/press-release/abbotts-firstinclass-mitraclip-device-now-available-for-us-patients.htm. Published October 25, 2013. Accessed October 25, 2013.
6. Ott C, Mahfoud F, Schmid A, et al. Renal denervation in moderate treatment resistant hypertension. J Am Coll Cardiol. 2013;Epub ahead of print.
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Yael L. Maxwell is Senior Medical Journalist for TCTMD and Section Editor of TCTMD's Fellows Forum. She served as the inaugural…
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