Download Lower might be better – It matters how you get there, and in whom

EDITORIAL
European Heart Journal (2016) 37, 1380–1383
doi:10.1093/eurheartj/ehw102
Lower might be better – It matters how you get
there, and in whom
Jennifer G. Robinson*
University of Iowa, Iowa City, IA, USA
Online publish-ahead-of-print 29 March 2016
This editorial refers to ‘Percent reduction in LDL cholesterol following high-intensity statin therapy: potential
implications for guidelines and for the prescription of
emerging lipid-lowering agents’†, by P.M. Ridker et al., on
page 1373.
Cholesterol treatment guidelines will continue evolving as new evidence emerges from randomized trials. Statins have been shown
to reduce cardiovascular events in progressively lower risk patient
populations with progressively lower entry and on-treatment
LDL-cholesterol (LDC-C) levels. This evidence was interpreted to
support further reductions in LDL-C treatment goals.1,2 When trials
demonstrated that high intensity statins reduced cardiovascular
events more than moderate intensity statins, some guidelines recommended a ≥50% LDL-C reduction as an alternative treatment
objective for high risk patients, reflecting the average reduction in
LDL-C expected from high intensity statins.2 – 4 However, substantial heterogeneity in treatment response has been reported. In a
meta-analysis of eight cardiovascular outcomes trials by Boekholdt
et al., approximately half of patients obtained a ≥50% reduction in
LDL-C with a high intensity statin.5 Greater relative risk reductions
(RRRs) occurred with progressively lower achieved LDL-C, with the
greatest RRR when LDL-C was ,1.3 mmol (50 mg/dL).5
The post-hoc analysis of the Justification for the Use of statins in
Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)
by Ridker et al. in this issue of the journal extends this literature by
exploring the relationship between percentage LDL-C reduction
with the high intensity statin, rosuvastatin 20 mg, and reduction in
the risk of cardiovascular events.6 Percentage LDL-C changes with
rosuvastatin ranged from modest increases to .80% reductions
in LDL-C, with 46% experiencing a ≥50% reduction in LDL-C.
Heterogeneity in non-HDL-C and apo B response also occurred,
although ≥50% reductions were less likely to occur than for
LDL-C. LDL-C reductions of ≥50% were more likely to occur in
women, Caucasians, non-smokers, hypertensives, and those with
higher baseline LDL-C levels or a premature family history of coronary heart disease (CHD). How much of the variation was due to biological response or to adherence cannot be determined from this
analysis. Approximately 25% of JUPITER participants were not taking their study pills by the end of the trial,7 and data were not shown
to evaluate conclusively the role of adherence in percentage LDL-C
reduction.
Not surprisingly, those achieving a ≥50% reduction in LDL-C
from rosuvastatin experienced a greater relative reduction in cardiovascular events than those achieving a .0% to ,50% reduction,
or no reduction in LDL-C. This is consistent with the Cholesterol
Treatment Trialists (CTT) meta-analysis of statin trials, where the
relative reduction in cardiovascular risk (RRR) is proportional to
the magnitude of LDL-C reduction.8 In the Ridker analysis, an
RRR of 39% was observed for those with a ,50% LDL-C reduction
and a 59% RRR was observed for those with a ≥50% risk reduction
in LDL-C. These RRRs are substantially higher than expected from
the magnitude of LDL-C lowering observed by the CTT where each
39 mg/dL (1 mmol/L) reduction in LDL-C is associated with a 21%
reduction in major cardiovascular events.8 Visually approximating
the medians from Figure 1 in the Ridker paper, the ,50% LDL-C
reduction group has an 1 mmol/L (40 mg/dL; 37%) reduction in
LDL-C, and the ≥50% LDL-C reduction group had an 1.7 mmol/L
(64 mg/dL; 59%) reduction in LDL-C; expected RRRs from CTT association would be 21% and 34%, much lower than reported in Ridker’s
analysis.
The much higher than expected RRRs reported in Ridker’s analysis
should be interpreted with caution. JUPITER was stopped early for
benefit, which may have inflated the observed RRRs; analyses of
trials stopped early for benefit on average are associated with a
30% higher RRR than trials that are not.9 Alternatively, the higher
than expected RRRs could be due to the low LDL-C levels at enrolment [,3.4 mmol/L (130 mg/dL), with a median LDL-C of 2.8 mmol/L
(108 mg/dL)], and thus lower achieved LDL-C levels on high intensity
statin therapy. Greater RRRs with lower achieved LDL-C levels are
consistent with the meta-analysis by Boekholdt et al. cited above, as
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
†
doi:10.1093/eurheartj/ehw046.
* Corresponding author. Department of Epidemiology, College of Public Health, University of Iowa, 145 N Riverside Drive S455 CPHB, Iowa City, IA 52242-2007, USA.
Tel: +1 319 384 1563, Fax: +1 319 384 4155, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
Editorial
Figure 1 Achieved LDL-cholesterol (LDL-C) levels (black triangle) when initial LDL-C levels of 190 mg/dL (4.9 mmol/L),
160 mg/dL (4.2 mmol/L), 130 mg/dL (3.4 mmol/L), 100 mg/dL
(2.6 mmol/L), or 70 mg/dL (1.8 mmol/L) are reduced by 20% or
50%, and the expected number needed to treat to prevent one
cardiovascular event (NNT) for the anticipated relative reduction
in the risk of cardiovascular events for a given level of absolute risk
and magnitude of LDL-C lowering based on the Cholesterol Treatment Trialists meta-analysis (adapted from Cholesterol Treatment
Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from
90,056 participants in 14 randomised trials of statins. Lancet
2005;366:1267 – 1278; data from Cannon et al.,16 Robinson
et al.,12 and Sabatine et al.13
well as a meta-analysis of coronary intravascular ultrasound trials
where progressively higher rates of atherosclerotic regression occurred with LDL-C levels ,0.4 mmol/L (15 mg/dL). 5,10 Alternatively,
it could be that those with an elevated pro-inflammatory state (study
inclusion on the basis of elevated C-reactive protein .2 mg/L) respond more robustly, or earlier, to statin therapy.
Several clinical questions remain after this analysis. The authors
suggest that a ,50% LDL-C reduction with a high intensity statin
may indicate a population that could benefit from the addition of
a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor
to reduce cardiovascular risk further. Inhibition with PCSK9 monoclonal antibodies reduces LDL-C by an additional 45 – 70% when
added to statin therapy.11 Ridker et al. overlook several important
concepts that will influence the potential for a patient to experience
a meaningful cardiovascular risk reduction benefit from added
LDL-C-lowering therapy: (i) that percentage LDL-C reduction
results in widely different magnitudes of LDL-C reduction in
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mmol/L (or mg/dL), depending on the pre-treatment LDL-C level;
(ii) that it is the magnitude of LDL-C reduction in mmol/L that is
associated with relative reduction in cardiovascular events; and
(iii) that absolute risk reduction (and therefore the number needed
to treat to prevent one cardiovascular event, or NNT) is a function
of a patient’s level of risk and the RRR.
Preliminary data from two PCSK9 monoclonal antibody efficacy
trials of 11–18 months duration suggest that these agents reduce cardiovascular events by 50% when mean LDL-C levels are reduced
from 3.1 mmol/L (120 mg/dL) to 1.3 mmol/L (50 mg/dL).12,13 The
confidence intervals in both trials included the 38% reduction in RRR
expected from a 1.8 mmol/L (70 mg/dL) reduction in LDL-C from the
CTT meta-analysis. Ongoing cardiovascular outcomes trials will probably have lower RRRs than were observed in the efficacy trials since
they are evaluating the effect of PCSK9 monoclonal antibodies added
to background maximal statin therapy, and baseline LDL-C levels are
expected to be well under 2.6 mmol/L (100 mg/dL).14,15 Ezetimibe is
currently the only non-statin shown clearly to reduce cardiovascular
events when added to background statin therapy in a large cardiovascular outcomes trial, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).16 Ezetimibe lowers LDL-C by
an additional 20–25% when added to background statin therapy, and
appears to reduce cardiovascular events as expected from the CTT
meta-analysis.16,17
As we enter the era of personalized medicine, treatment decisions can, and should, be tailored to an individual patient’s level of
risk, LDL-C level, and the anticipated benefits and adverse effects
from added therapy. This ‘net benefit’ approach was introduced in
the 2013 ACC/AHA (American College of Cardiology/American
Heart Association) cholesterol guideline and expanded upon in a
subsequent European Heart Journal publication evaluating the results
of IMPROVE-IT by this author.4,18 Figure 1 illustrates how decisionmaking could be based on net benefit as estimated by NNT. Adding
ezetimibe or another agent that reduces LDL-C by 20% without
significant adverse effects may be of marginal benefit (NNT .50) in
high risk patients with LDL-C ,130 mg/dL or very high risk patients
with LDL-C levels close to 70 mg/dL. High risk patients with a 10%
5-year (e.g. 20% 10-year) atherosclerotic cardiovascular disease risk
would be roughly similar to the non-diabetic chronic CHD patients
in the Treating-to-New Targets Trial who had 5-year atherosclerotic
cardiovascular disease event rates of 9.7% on atorvastatin 10 mg,
while diabetic patients with CHD in TNT had a 5-year event rate
of 17.9% on atorvastatin 10 mg.19 The NNT cut-off point of 50
comes from a survey of physicians who considered that to be the
maximum number of people it would be reasonable to treat to prevent one event. On the other hand, the accompanying survey of patients found that they considered an maximum reasonable NNT to
be 30.20 This supports shared decision-making within the context of
a clinician – patient discussion that considers the potential for net
benefit and patient preferences before initiating additional non-statin
cardiovascular risk reduction therapies.
A greater LDL-C reduction of 50%, such as can be achieved with
PCSK9 monoclonal antibodies, is more likely to have an acceptable
margin of cardiovascular benefit (NNT ,50) in high risk and very
high risk patients with LDL-C levels as low as 70 mg/dL, and in
moderate risk patients with LDL-C levels .130 mg/dL (Figure 1).
Unfortunately, PCSK9 monoclonal antibodies are expensive and
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exceed commonly accepted cost-effectiveness thresholds.21 For
example, among patients with cardiovascular disease and LDL-C
.70 mg/dL, the NNT was 21 and the cost-effectiveness was
US$302 000 per quality-adjusted life year (QALY) at the US pricing
of US$14 000 per year. An annual price of US$7735 would meet
the US$150 000 per QALY threshold. However, this assumes a 50%
reduction in cardiovascular events derived from the preliminary
data from the two efficacy/safety trials. If the RRRs in the PCSK9
monoclonal antibody cardiovascular outcomes trials are closer
to 25% due to the lower baseline LDL-C levels, then QALY will
probably exceed half a million US dollars for high risk patients unless
substantial discounting occurs.
This analysis of JUPITER could also be considered supportive of
LDL-C treatment ‘targets’ much lower than are currently recommended for primary (or secondary) prevention. The achieved
LDL-C level was 67 mg/dL in the ,50% group and 45 mg/dL in
the ≥50% LDL-C reduction group. Notably, higher rates of cardiovascular disease events occurred in those with LDL-C .50 but
,75 mg/dL (per 1000 patient-years: 18.4% placebo, 19.8% no reduction, 5.4% ,50% reduction, 4.1% ≥50% reduction) than in
the trial population as a whole with median LDL-C 108 (95 –119)
mg/dL (11.2, 9.2, 6.7, and 4.8, respectively). However, Figure 1 also
suggests one-size-fits all LDL-C goals may at best be arbitrary, and, at
worst, unlikely to benefit the individual patient. Taken together, these
data appear to support moving away completely from LDL-C treatment thresholds for primary prevention (.115 mg/dL in the European guideline,2 .100 mg/dL in other guidelines,22 or .70 mg/dl
in the 2013 ACC/AHA cholesterol guideline4) and instead focusing
on atherosclerotic cardiovascular disease risk and the potential for
net benefit guiding statin initiation.
In conclusion, accumulating evidence suggests future guidelines
should move toward personalizing cardiovascular risk reduction
therapies based on the potential for a net benefit for an individual
patient. For cholesterol-lowering therapies, lower LDL-C might
be better, but it matters how you get there and in whom, and should
be approached within the context of shared decision-making.
Conflict of interest: in the past year, J.G.R. has received research
grants to her Institution from: Amarin, Amgen, Astra-Zeneca, Eli
Lilly, Esai, Glaxo-Smith Kline, Merck, Pfizer, Regeneron/Sanofi, and
Takeda, and is a consultant for Akcea/Isis, Amgen, Eli Lilly, Esperion,
Merck, Pfizer, and Regeneron/Sanofi.
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CARDIOVASCULAR FLASHLIGHT
doi:10.1093/eurheartj/ehv171
Online publish-ahead-of-print 20 May 2015
.............................................................................................................................................................................
Cardiac perforation as a rare complication of acupuncture
Olivier Wigger1, Stefan Stortecky1*, Henriette Most2, and Lars Englberger2
1
Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, Bern 3010, Switzerland; and 2Department of Cardiovascular Surgery,
Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland
* Corresponding author. Email: [email protected]
A previously healthy 51-year-old female was
referred to the emergency department with ongoing chest pain and dyspnoea. The ECG showed
non-significant ST-segment elevations and PQ
depression in the limb leads with reciprocal PQ
elevation and ST depression in aVR (Panel A), suggestive for acute pericarditis. As repetitive blood
sampling assessment showed a relevant increase
in high-sensitivity Troponin, a coronary angiography was performed to rule out significant coronary artery disease. While the coronary arteries
were free from atheromatous plaques, the
fluoroscopic images showed a needle-shaped
foreign body projecting on the left ventricle (Panel B). Transthoracic echocardiography was not
able to identify the cause of the foreign body,
but computed tomography scan confirmed the
presence of a needle-shaped radiopaque structure perforating the left ventricle and protruding
into the left lower lobe of the lung (Panel C). After discussing the imaging findings as a potential reason for the clinical symptoms, the
patient immediately mentioned an acupuncture treatment some days ago. Acupuncture was performed by a non-professional and close
friend to treat her chronic musculo-skeletal pain. Cardiac surgery was immediately performed, during which a left-sided haemothorax
was evacuated and the thin needle (0.2 × 75 mm) completely removed without cardiopulmonary bypass (Panel D). Patient recovery was
fast and uneventful and she was discharged on Day 4 after surgery.
Thoracic therapeutic acupuncture could be associated with potential life-threatening complications in inexperienced hands and should
only be performed by trained experts in the field.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].