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European Society of Cardiology 2017
This year’s European Society of Cardiology (ESC) 2017 Congress hosted nearly 27,000 delegates, attending 500 expert sessions, from August 26 to 30 in Barcelona. We review a variety of key sessions highlighted in ESC press conferences. These sessions focused on examining strategies for reducing inflammation, lowering cardiovascular risk, providing anticoagulation in atrial fibrillation, lowering cholesterol, assessing sildenafil for pulmonary hypertension following valve repair, and evaluating renal denervation for hypertension.
Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)
Canakinumab (Ilaris, Novartis), a human monoclonal antibody that suppresses inflammation by neutralizing interleukin (IL)-1β signaling, reduced cardiovascular event rates and, in an exploratory analysis, lowered rates of death from any cancer, according to Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) results. Canakinumab is typically used to treat rare inherited conditions associated with overproduction of IL-1β, Dr. Ridker said in an ESC press conference.
In CANTOS, patients (N = 10,061) with prior myocardial infarction and persisting elevated levels of high-sensitivity C-reactive protein (hsCRP) were randomized to placebo or 50 mg, 150 mg, or 300 mg of canakinumab given subcutaneously once every three months. All were receiving high doses of statins. The number of major adverse cardiovascular events (MACE), defined as the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, was the primary endpoint.
While canakinumab had no effect on high- or low-density lipoprotein-cholesterol levels, nor any effect on triglycerides, its effects on hsCRP were dose dependent and similarly high for the 150-mg and 300-mg subcutaneous doses given once every three months (39% reduction).
After four years of follow-up, MACE was significantly reduced by about 15% in the canakinumab 150-mg and 300-mg groups compared with the placebo group (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76–0.96; P = 0.007). Also, the need for revascularization procedures was reduced by 30% among those receiving canakinumab (P < 0.0001). Furthermore, risk was reduced most among those patients whose hsCRP decreases at three months were 1.8 mg/L (the median) or greater (HR, 0.73; 95% CI, 0.63–0.83; P = 0.0001). Residual inflammatory risk, Dr. Ridker noted, was found in 43% and 47% of patients enrolled in the PROVE-IT and IMPROVE-IT trials, respectively. Residual cholesterol risk, in those same trials, was present in about 28% of patients.
Seeking other potential anti-inflammatory effects of canakinumab, CANTOS investigators conducted exploratory analyses of cancer risk. They found a 51% reduction in death from any cancer with canakinumab 300 mg (P = 0.0009), a 67% reduction in the incidence of lung cancer (P = 0.00008), and a fatal lung cancer reduction of 77% (P = 0.0002). The latter finding is consistent with experimental data relating IL-1 to the progression and invasiveness of certain tumors, particularly lung cancer. Dr. Ridker said that inflammation in the tumor microenvironment mediated by IL-1β is hypothesized to play a major role in cancer invasiveness, progression, and metastases. “The data on cancer rates point to the possibility of slowing the progression of certain cancers, but these are exploratory findings that need replication,” he commented. He said that CANTOS patients had been free of previously diagnosed cancer.
Dr. Ridker also reported a significantly higher incidence of fatal infection and sepsis with canakinumab than with placebo, as well as a reduction in platelet counts, but with no increase in bleeding risk. There was no significant difference between the canakinumab groups and the placebo group in all-cause mortality. No statistically or clinically significant hepatic toxic effects were noted. Beneficial effects of canakinumab were also observed in arthritis, gout, and osteoarthritis and were consistent with well-described effects of the IL-1 and IL-6 pathways in these disorders.
Dr. Ridker concluded, “These data provide proof that inflammation inhibition, in the absence of lipid lowering, can improve atherothrombotic outcomes and potentially alter the progression of some fatal cancers.”
The COMPASS Trial: Rivaroxaban With or Without Aspirin in Stable Cardiovascular Disease
In patients with stable cardiovascular disease (including peripheral artery disease), 2.5 mg rivaroxaban (Xarelto, Janssen Pharmaceuticals) twice daily plus 100 mg aspirin once daily compared with 100 mg aspirin once daily alone reduced cardiovascular death, stroke, and myocardial infarction. The combination produced higher rates of major bleeding, but fatal, intracranial, or critical organ bleeding was not significantly increased, Dr. Eikelboom said in an ESC press conference.
Dr. Eikelboom pointed out that cardiovascular disease affects 4% of the world population and causes 18 million deaths per year. While aspirin is used widely for secondary prevention, it is only modestly effective. The ATLAS ACS-2 TIMI 51 trial showed rivaroxaban reduced mortality in patients with post-acute coronary syndromes.
The COMPASS trial included 27,395 patients from 33 countries treated at 602 centers in North America, South America, Asia, Western Europe, Eastern Europe, South Africa, and Australia. They were randomized 1:1:1 to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily; rivaroxaban 5 mg twice daily; or standard therapy with aspirin 100 mg once daily. The primary endpoint was a composite of cardiovascular death, stroke, or myocardial infarction.
The data safety monitoring board for the trial, due to the clear superiority of the rivaroxaban-plus-aspirin arm, recommended cessation of treatment in both monotherapy arms. The primary endpoint rates were 4.1%, 4.9%, and 5.4% in the combination, rivaroxaban alone, and aspirin alone arms, respectively. Comparison of the rivaroxaban arm and the aspirin arm revealed no differences (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.79–1.03; P = 0.12). The hazard ratio in the rivaroxaban/aspirin versus aspirin arm was 0.76 (95% CI, 0.66–0.86; P < 0.0001).
Both rivaroxaban-containing arms had significantly higher major bleeding rates (P < 0.0001): 3.1%, 2.8%, and 1.9% for the combination arm, rivaroxaban arm, and aspirin arm, respectively. A net clinical benefit analysis taking into account primary and severe bleeding events showed a significantly lower rate of risk for the combination arm (4.7% versus 5.9%; HR, 0.80; 95% CI, 0.70–0.91; P = 0.0005).
“The substantial benefits seen with rivaroxaban and aspirin support the approach of using low doses of the two treatments in combination,” Dr. Eikelboom concluded. He commented further, “Recent trials in other disease areas have demonstrated substantial benefits from using low doses of a combination of drugs, and this concept is now further supported by the results of COMPASS.”
Apixaban Versus Conventional Therapy In Anticoagulation-Naïve Patients With Atrial Fibrillation Undergoing Cardioversion: The EMANATE Trial
“In patients with atrial fibrillation undergoing cardioversion, apixaban [Eliquis, Bristol-Myers Squibb] with or without a loading dose was safe, resulting in few bleeding events and less strokes than conventional anticoagulant therapy,” Dr. Ezekowitz said while presenting results of the EMANATE trial in an ESC press conference. Patients (N = 1,500) enrolled in EMANATE were randomized open-label to apixaban 5 mg twice daily or usual care with heparin/warfarin. All participants were anticoagulation naïve; at the discretion of the treating physician, they received a loading dose of apixaban. Uniquely, EMANATE investigators assessed more immediate cardioversion (less than 48 hours), avoiding prolonged periods of precardioversion anticoagulation.
The goal of anticoagulation in the setting of cardioversion, Dr. Ezekowitz said, is to prevent stroke and systemic embolism without causing bleeding. While patients scheduled for cardioversion of atrial fibrillation typically receive heparin and/or warfarin to reduce stroke risk, both heparin and warfarin have drawbacks, with heparin being administered via injection and warfarin having a delayed therapeutic effect. Apixaban has rapid onset and is given orally. It has not been tested previously in this population, however.
In EMANATE patients, cardioversion could be performed two hours after an apixaban loading dose of 10 mg (n = 11) or 5 mg (n = 331) in the presence of two of the following: age 80 years and older, weight of 60 kg or less, serum creatinine of 1.5 mg/dL or greater (133 micromol/L). Anticoagulants were administered for 30 days after cardioversion or for a maximum of 90 days if cardioversion was not performed. The primary endpoints were combined stroke and systemic embolism, major bleeding, and clinically relevant nonmajor bleeding at 90 days. Anticoagulation duration was less than 48 hours in all patients, and 61% received no anticoagulation prior to randomization.
Stroke/embolic event rates favored those receiving apixaban after 90 days, with no events occurring in the apixaban group (n = 753) versus six events (five ischemic strokes and one hemorrhagic stroke) in the heparin/warfarin group (n = 747) (P = 0.0164). Three major bleeds occurred in the apixaban group versus six in the heparin/warfarin group. Clinically significant nonmajor bleeding occurred in 11 patients in the apixaban group and in 13 usual-care patients. In the apixaban loading-dose subgroup, there were no strokes or systemic embolic events, one death, one major bleed, and four clinically relevant nonmajor bleeds.
“We expect these findings will be translated into clinical practice,” Dr. Ezekowitz said.
FOURIER: Safe and Effective Extreme LDL-Cholesterol Lowering With Evolocumab
Prescribers should target considerably lower levels of low-density lipoprotein-cholesterol (LDL-C) than are currently recommended for patients with atherosclerotic cardiovascular disease based on a new analysis of the FOURIER trial, Dr. Giugliano said at an ESC press briefing. Patients in FOURIER had stable atherosclerotic cardiovascular disease and were treated with evolocumab (Repatha, Amgen), a proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, or placebo on top of background statin therapy.
Dr. Giugliano noted that LDL-C is a well-established risk factor for atherosclerotic cardiovascular disease. “How much one should or safely can lower this risk factor remains debated,” he said. LDL-C reductions with evolocumab to a median of 0.8 mmol/L at a median follow-up of 2.2 years had been revealed in earlier publication of FOURIER results.1 This showed that LDL-C can now be reduced to unprecedented low levels below 1 mM with statins plus PCSK9 inhibition. The cholesterol level decrease, a 59% decline compared with placebo (P < 0.00001), was accompanied by a significant reduction in cardiovascular events, from 14.6% with placebo to 12.6% with evolocumab (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.79–0.92, P < 0.0001), including combined cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization.
For this exploratory analysis, investigators compared cardiovascular events in patients attaining LDL-C levels of 2.6 mM or higher (less than 10 mg/dL) at four weeks with rates in patients achieving 0.26 mM or lower. Analysis showed the primary endpoint rate to be significantly lower in the group with greater lowering of LDL-C (11.9% versus 7.3%; HR, 0.69; 95% CI, 0.49–0.97; P = 0.03). Safety, however, was equivalent in the two groups, with serious adverse event rates of 23.3% and 22.8% (HR, 0.94; 95% CI, 0.74–1.20; P = 0.61). Both groups had identical discontinuation rates of 3.4% for adverse events.
Reductions in LDL-C to well below current recommendations are supported by FOURIER data, Dr. Giugliano stated. FOURIER showed a strong linear relationship between achieved LDL-C levels and cardiovascular event rates.
“We should target considerably lower LDL-cholesterol than is currently recommended for our patients with atherosclerotic cardiovascular disease,” Dr. Giugliano concluded.
PRECISION-ABPM: Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement Trial
When physicians prescribe drugs with arthritis-mitigating benefits, they also need to consider the potential cardiovascular hazards of those drugs, according to findings from the PRECISION-ABPM trial. That analysis, Dr. Ruschitzka said at an ESC press briefing, showed further evidence that nonselective nonsteroidal anti-inflammatory drugs (NSAIDS), especially ibuprofen, increase both systolic blood pressure and new-onset hypertension compared to celecoxib.
In the United States and Europe, nearly 100 million prescriptions for NSAIDS are written each year. These agents, however, aside from their analgesic effects through inhibiting cyclooxygenase, may exert off-target cardiovascular effects. To assess risks, PRECISION-ABPM investigators compared the COX-2 inhibitor celecoxib (100 mg to 200 mg twice daily) to two widely used NSAIDs, naproxen (375 mg to 500 mg twice daily) and ibuprofen (600 mg to 800 mg three times daily). The trial included 444 patients with arthritis and either known coronary artery disease or relatively high cardiovascular risk. Among them, 408 (92%) had osteoarthritis and 36 (8%) had rheumatoid arthritis. The change from baseline in 24-hour mean systolic blood pressure after four months of treatment was the primary outcome measure.
With celecoxib, average 24-hour systolic blood pressure went down by 0.3 mm Hg, but it went up with both ibuprofen and naproxen, by 3.7 mm Hg and 1.6 mm Hg, respectively. The difference between ibuprofen and celecoxib was statistically significant (P = 0.009). An additional analysis showed that 23% of patients whose systolic blood pressure was in the normal range at baseline became hypertensive as a consequence of receiving ibuprofen. The percentage for celecoxib was 10.3% and for naproxen was 19.0%. Differences for celecoxib versus ibuprofen and naproxen were both significant (P = 0.004 and P = 0.03, respectively).
“Even relatively small changes in blood pressure may impact cardiovascular morbidity and mortality,” Dr. Ruschitzka said. “Since decreasing systolic blood pressure by just 2 mm Hg lowers stroke mortality by 10% and ischemic heart disease mortality by 7%, increases in systolic blood pressure associated with NSAIDs as observed in PRECISION-ABPM should be considered clinically relevant.” He noted further, “The current findings suggest that the elevated cardiovascular risk with NSAIDs may be partly due to drug-specific increases in blood pressure.” That suggestion is contrary to the widely held hypothesis that the adverse cardiovascular effects of NSAIDs relate directly to their effects on platelets and endothelial cells.
Effect of Sildenafil on Clinical Outcomes in Patients With Corrected Valvular Heart Disease And Residual Pulmonary Hypertension: The Sildenafil for Improving Outcomes After Valvular Correction (SIOVAC) Trial
Composite clinical scores worsened and risk of hospitalization was doubled compared with placebo among patients receiving sildenafil (Viagra, Pfizer) for residual pulmonary hypertension after correction of a valvular lesion in the SIOVAC trial.
For valvular disease, the only established treatment is surgical or percutaneous repair or replacement, Dr. Bermejo said in an ESC press conference. “But symptoms often remain or reappear in the long term. Residual pulmonary hypertension is the most important risk factor for death and disability after successful correction of the valvular lesion,” he said.
While sildenafil, a potent vasodilator, is typically used to treat erectile dysfunction, it has proven to be useful for off-label treatment of retrograde pulmonary hypertension, although with inconsistent results. Chronic administration of sildenafil in this type of pulmonary hypertension had not been tested previously in clinical trials. SIOVAC investigators enrolled 200 patients with residual pulmonary hypertension after correction of a valvular lesion and randomized them double-blind to sildenafil 40 mg (three times daily) or placebo for six months. The trial was conducted in 18 tertiary public hospitals in Spain. All patients had pulmonary hypertension confirmed by cardiac catheterization. The primary endpoint was the composite clinical score, a measure combining all-cause death, hospital admission for heart failure, worsening exercise tolerance (measured by change in functional class), and feeling worse than when starting the medication (based on change in a self-assessment score).
Analysis of SIOVAC findings at six months revealed no benefits for sildenafil. “We were unable to identify any particular subset of patients who could potentially benefit from sildenafil,” Dr. Bermejo said. Composite clinical scores had declined from baseline in 15% of patients receiving placebo and in 33% of patients receiving sildenafil (odds ratio for improvement, 0.39; 95% confidence interval [CI], 0.22–0.67; P < 0.001). Clinical status improved in 27% of patients receiving sildenafil and in 44% of patients receiving placebo. The hazard ratio for experiencing a major clinical event for sildenafil versus placebo was 2.0 (95% CI, 1.0–4.0; P = 0.044), and hospital admissions for decompensated heart failure were doubled in the sildenafil group.
Dr. Bermejo concluded, “Off-label use of sildenafil in patients with left heart disease pulmonary hypertension due to valvular disease should be discouraged.” He added that because the disease is strongly associated with age, valvular heart disease is likely to be the next cardiac epidemic given the large aging population worldwide.
Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension In the Absence Of Antihypertensive Medications (SPYRAL HTN-OFF MED): A Randomized, Sham-Controlled, Proof-of-Concept Trial
Among patients with mild-to-moderate hypertension who were not receiving any background antihypertensive medications, renal denervation led to clinically meaningful blood pressure reductions compared with sham control after three months in the SPYRAL HTN-OFF MED trial. Renal denervation, Dr. Böhm noted in an ESC press conference, targets the sympathetic nervous system to reduce blood pressure. He pointed out that risks for cardiovascular events and stroke increase for many among the one-third of adults with hypertension whose blood pressure remains uncontrolled.
The earlier SYMPLICITY HTN-3 trial failed to demonstrate significant blood pressure lowering for renal denervation. Causes for that failure are said to include variance in medication adherence, incomplete denervation of the renal arteries, and inclusion of patients with isolated systolic hypertension, which is known to be hyporesponsive to renal denervation. In SPYRAL HTN-OFF MED, patients received no antihypertensive medications. Other remedies to the SYMPLICITY HTN-3 shortcomings were evaluation of adherence through serum and urine testing, inclusion limited only to patients with less severe hypertension, exclusion of isolated systolic hypertension, and use of only highly experienced operators to guarantee more thorough denervation procedures.
SPYRAL HTN-OFF MED was an international, multicenter, prospective, randomized, single-blind trial. All patients had uncontrolled hypertension, defined as an office systolic blood pressure between 150 and 180 mm Hg and diastolic blood pressure greater than than 90 mm Hg, and a 24-hour mean systolic blood pressure between 140 and 170 mm Hg. Eligible patients were drug-naïve or had discontinued their antihypertensive medications. They were enrolled at 21 centers in the U.S., Europe, Japan, and Australia. Eligible patients were randomized to renal denervation in the main renal arteries and its branches, or to a sham procedure. The primary endpoint was blood pressure change from baseline at three months post-procedure.
“All blood pressure measurements within the renal denervation arm showed statistically significant reductions from baseline, while none of the measurements in the sham arm were significantly reduced from baseline,” Dr. Böhm reported. In the first 80 patients, office-based systolic and diastolic blood pressure declined by 10.0 mm Hg (P < 0.001) and 5.3 mm Hg (P = 0.008) in the renal denervation arm, respectively, compared with a decline of 2.3 mm Hg (P = not significant [NS]) and 0.3 mm Hg (P = NS) in the sham arm, respectively. Similar reductions in the active treatment arm were confirmed with 24-hour ambulatory blood pressure monitoring.
There were no major safety events in either arm of the trial.
Dr. Böhm concluded, “The effectiveness of renal denervation in this study may have been due to the new procedural approach, which aimed to achieve complete denervation, and the fact that patients were not taking antihypertensive medications. That may have confounded the results of previous studies.”
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376(18):1713–1722. doi: 10.1056/NEJMoa1615664.