Transcript BP Goals in CKD

Highlights from the Medical Literature:
Top 10 Cardiovascular Articles from 2012
Michael J Bloch, MD, FACP, FVM, FASH
Department of Medicine,
University of Nevada School of Medicine
Faculty Disclosures
Michael J. Bloch, M.D.
• Consultant: Astra-Zeneca; Takeda; Aegerion
• Speaker’s Bureau/Honoraria: AstraZeneca,
Takeda, Boeringer-Ingellheim, Daiichi-Sankyo,
Liposcience
Learning Objective
At the conclusion of this session, the learner should be able
to:
•Explore specific findings that have been published in the
cardiovascular literature within the past 12 months in order
to apply relevant findings to his or her clinical practice
Studies In Clinical Hypertension
Bedtime dosing of antihypertensive
medications reduces cardiovascular risk in
chronic kidney disease
Hermida RC, et al. J Am Soc Nephrol.
2011;22(12):2313 2321.
Nocturnal Dosing BP Rx
Background:
•Previous studies with ambulatory BP monitoring (ABPM)
have demonstrated that the mean sleep-time BP is a better
predictor of CV events than is the mean daytime or 24-hr
BP.
•BP Rx has traditionally been dosed primarily in the
morning.
•Some recent studies have suggested that restoration of
the normal circadian “dipping” pattern of nocturnal BP by
giving some of the antihypertensive rx at bedtime may lead
to lower CV risk
•Nocturnal hypertension common in CKD
Nocturnal Dosing BP Rx
Question:
In hypertensive patients with CKD, does giving at
least one of the HTN medications at bedtime
reduce CV risk compared to giving all medications
upon waking?
Nocturnal Dosing BP Rx
Methods:
•661 hypertensive patients with mild CKD (about ½ with Cr
Cl >60 ml/min but + microalbuminuria)
•About 2/3 were “nondippers” (BP did not exhibit normal
circadian drop at night)
•All patients were on once daily BP Rx.
•Randomized to take at least one BP rx at bedtime or to
continue taking them all upon awaking.
•ABPM was done for 48 hours at baseline and at least
yearly.
•Median follow-up was 5.4 years
•Primary outcome was total CV events (CV death, MI, and
stroke)
Nocturnal Dosing BP Rx
Results:
• The adjusted hazard ratio for major CV events
was 0.28 for nocturnal vs morning dosing
• Major CV events were 1.45%/yr for the AM
dosing vs 0.51%/yr for bedtime dosing
Nocturnal Dosing BP Rx
Results:
•The awake BP mean was no different between
the groups
•However, the sleep systolic BP mean was 6
mmHg lower in the bedtime dose group, and a
greater number reverted to a “dipping” pattern
(59% vs 29% in AM dose group at end of study)
Nocturnal Dosing BP Rx
Conclusions:
• In hypertensive patients with mild CKD on once
daily BP medications, moving at least one of the
doses to bedtime reduces CV morbidity
Caveats:
• Clinic BPs in both groups at end of study were
above accepted targets (mean 146/80).
• It is unclear if the magnitude of benefit would be
as great if all patients had been more
aggressively treated.
Nocturnal Dosing BP Rx
Clinical Implications:
•While awaiting further data:
• In patients with mild CKD (and possibly others), it’s
reasonable to switch at least one of their BP rx to
bedtime dosing (unless the patient is at high risk for
falls in the night or for decreased compliance)
• What about other hypertensive populations?
• Do we need to do more ABPM?
Intensive BP and/or Glucose Control Did
Not Reduce Microvascular Events in
Hypertensive Type 2 Diabetics
Post-Hoc Analysis of ACCORD BP
Ismail-Beigi F, et al, Kidney Int. 2012;81:58694.
ACCORD BP - Microvascular
Background:
• From the ACCORD BP study we know that in
patients with hypertension and type 2 diabetes
more intensive treatment of BP (goal <120) did
not reduce the incidence of macrovascular
events as compared to less intensive treatment
of BP (goal <140)
Question:
• What about microvascular events?
ACCORD BP - Microvascular
Methods:
•Post-hoc analysis of ACCORD BP study
•4733 patients 40-79 years of age with T2DM and
HTN randomized to SBP goal <120 mmHg or <140
mmHg
•Patients also randomized to hbA1C target of
<6.0% or <7.0-7.9%
•Mean f/u 4.7 years
•Primary endpoint – composite of renal and retinal
outcomes
ACCORD BP – Microvascular - Results
Outcomes
Intensive BP
Standard BP
11.4%
10.9%
+7.5%
ns
Incident
Microalbuminuria
21%
25%
-14%
29
Incident
macroalbuminuria
5.7%
7.1%
-18%
ns
Primary Composite
RRR (RRI) NNT (NNH)
The effect of BP control was not modified by
intensity of glycemic control for any outcome
ACCORD BP - Microvascular
Conclusion:
• Intensive BP control did not reduce macro- or
micro-vascular events more than standard BP
control in patients with T2DM and hypertension,
regardless of intensity of glycemic control
Caveats
• Event rates were low
• Follow-up was relatively short
• Subjects also had great glycemic, lipid, and
tobacco control
ACCORD BP - Microvascular
Clinical Implications:
Systolic BP Goal
(mmHg)
Strength of
Evidence
Most Patients with
Diabetes
<140
Strong, based on
primary endpoint
Diabetes Patients
with Higher Stroke
Risk*
<120#
Less Strength, based
on secondary
endpoint
*Defined as personal or family history of TIA/stroke, smoker,
unable to tolerate statin therapy or antiplatelet therapy when
approprioate, LVH or poor glycemic control
#With close monitoring for bradycardia, hypotension, changes in
electrolytes, and worsening renal function
More Intensive BP Control May Not Be
Advantageous in Chronic Kidney Disease
(CKD)
The Kidney Early Evaluation Program
(KEEP)
Peralto CA, et al. Arch Intern Med
2012;172:41-47.
BP Goals in CKD - KEEP
Background:
• Guidelines have long suggested BP goal
<130/80 in patients with CKD
• This recommendation is mostly supported by
observational data and has been hard to support
with RCTs
Question:
• What is the optimal BP for a patient with CKD?
BP Goals in CKD - KEEP
Methods
• Nation-wide, community based observational
study enrolling adults with CKD or its major risk
factors
• As of 2000, KEEP included data on 16,121
persons with CKD (at least stage 3)
• US Renal Data System was used to capture
incidence of ESRD
• Primary Endpoint: Incident ESRD
• Follow-up = 2.7 years
BP Goals in CKD - KEEP
Results
• Only 2% of patients progressed to ESRD
• 48% of patients had baseline SBP>140 or DBP>90
• As compared to those with baseline SBP <130, only
patients with SBP >150 had increased risk of ESRD
• As compared to those with baseline DBP <75, only
patients with DBP >90 had increased risk of ESRD
• Patients with albuminuria represented only 20% of the
cohort, but accounted for 88% of ESRD
– Presence of albuminuria did not effect results of KEEP but
has been demonstrated to be a marker of response to
intensive BP control in other studies
BP Goals in CKD - KEEP
Conclusions:
•In patients with CKD, the hypothesis that more intensive
control of SBP to a goal of <130 mmHg decreases the
incidence of ESRD remains unproven
Caveats
•Short follow-up
•Cardiovascular events not meaured
•Observational study – hypothesis generating only
•Effect of albuminuria unclear and not consistent with
previous trials
BP Goals in CKD - KEEP
Clinical Implications
• BP is poorly controlled in patients with CKD
• BP target of <140/90 probably reasonable for
most patients with CKD
• Consider more aggressive therapy in those with
higher risk of progression to CKD, including
young age or presence of albuminuria
• Await results of NIH sponsored SPRINT study
– >9000 at risk patients with hypertension randomized
to SBP<140 vs SBP<120
– More than 40% of patients expected to have CKD
Renal Sympathetic Denervation for
Treatment of Drug Resistant Hypertension
One Year Results from Symplicity HTN-2
INVESTIGATIONAL
Esler MD, et al. Circulation 2012;126:2976-82.
Symplicity HTN-2
Background:
• Renal sympathetic nerve activation contributes
to the pathogenesis of hypertension
• Sympathectomy has been demonstrated to be
effective in treating resistant HTN, but with
considerable adverse events
Question:
• What is the benefit and risk of catheter based
renal denervation in patients with treatment
resistant hypertension?
Symplicity HTN-2
Symplicity HTN-2
Methods
• Eligible patients were on at least 3 BP meds and
had a baseline SBP >160mmHg
• Randomized to catheter based renal
denervation or medical management
• This report includes one year results of those
patients originally randomized to renal
denervation and patients who crossed over after
6 months due to poorly controlled BP
Symplicity HTN-2
Results:
Mean BP
Immediate Renal
Denervation (n=49)
Cross-Over Group
(n=35)
Before Procedure
178/96
190/99
6 Months After
Procedure
146/84
166/91
12 Months After
Procedure
150/87
n/a
Complications included one renal artery dissection
No significant changes in eGFR or cystatin c
Symplicity HTN-2
Conclusion
• Catheter based renal artery denervation led to
significant and sustained reductions in BP in
patients with poorly controlled resistant HTN at
baseline with limited potential for adverse events
Caveats
• Short follow-up, particularly for adverse events
• Unblinded
Symplicity HTN-2
Clinical Implications
• Catheter based renal denervation is an
investigational procedure that may have a role in
the treatment of uncontrolled resistant
hypertension in the future
• May be other indications, including heart failure
• Long term safety issues unknown
• Await results of Symplicity HTN-3
• RCT that includes sham renal denervation as control
group and include ABPM
Clinical Implications of Latest BP Trials
• Switching at least 1 BP med to night-time administration
may improve nocturnal BP control and reduce CV
events, at least in CKD
• Systolic BP goal of <140 mmHg may be reasonable for
most patients with T2DM
• Systolic BP goal of <140 mmHg may be reasonable for
most patients with CKD
• Catheter-based renal denervation is an investigational
procedure that may prove to be safe and effective in
treatment of poorly controlled resistant HTN
• Eagerly await future near-term publications in clinical
hypertension, including SPRINT, Symplicity HTN-3, and
JNC8
Studies In Clinical Lipidology
Another Investigational CETP Inhibitor Fails to
Demonstrate Reduction in Events in Patients
with Recent ACS
Dal-OUTCOMES
INVESTIGATIONAL
Schwartz GG, et al. New Engl J Med
2012;367:2089-99.
Dal-OUTCOMES
Background
• In observational analyses, higher HDL-C is associated
with lower risk of CHD events
• CETP inhibitors raise HDL-C significantly, but their
effects on CV outcomes is unclear
• Torcetrapib increased HDL-C, but failed to reduce CV
events, perhaps due to mild increase in BP and
aldosterone
Question:
• Would use of the CETP inhibitor dalcetrapib reduce CHD
events in patients with recent ACS?
Dal-OUTCOMES
Methods
• 15,871 patients with recent ACS
• Best available background risk reduction therapy
including target LDL-C of around 70 mg/dl with
statin therapy
• Randomized to dalcetrapib 600 mg daily or
placebo
• Primary endpoint = composite of fatal and
nonfatal CHD
• Mean follow-up = 31 months
Dal-OUTCOMES - Results
Lipid Levels
Primary Endpoint
Dal - OUTCOMES
Conclusion
• Despite an approximately 35% increase in HDLC, dalcetrapib did not reduce the risk of
recurrent CHD events in patients with recent
ACS with well controlled LDL-C
Clinical Implications:
• HDL-C is complicated
• Endpoint studies needed for lipid lowering drugs,
particularly those that have their primary effect
on HDL-C or LDL size
Studies In Anti-Platelet and Anticoagulant Therapy
Novel Anticoagulant Now Indicated to
Reduce Risk of Recurrent Venous
Thromboembolic Events
EINSTEIN DVT and PE Studies
Pooled Analysis As Presented at American
Society of Hematology 2012 Annual Meeting
(Harry Buller, MD)
Einstein Investigators. N Engl J Med. 2010;363:2499-510.
Einstein Investigators. N Engl J Med. 2012;366:1287-1297
Einstein DVT and PE
Background
• Three novel anticoaglulants (dabigratran, rivaroxaban,
and apixaban) are approved as alternatives to warfarin
to prevent stroke and systemic embolism in patients with
non-valvular atrial fibrillation
• DVT/PE is another indication for anticoagulation
Question
• How does the factor Xa inhibitor rivaroxaban compare to
warfarin in efficacy and safety for patients with a history
of venous thromboembolism (DVT or PE)?
Einstein DVT and PE
Methods
• Patients with a history of PE (n = 4832) or symptomatic
DVT (n = 3449)
• Randomized to
– Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg
daily
OR
– Standard therapy with enoxaparin followed by dose adjusted
warfarin with INR goal 2-3
• Primary efficacy endpoint = symptomatic recurrent
thromboembolic event (DVT or PE)
• Primary safety endpoint = major or clinically relevant
non-major bleeding
Einstein DVT and PE – Pooled Results
Outcome
Rivaroxaban (%)
Standard
Therapy (%)
Hazard Ratio
(HR) with 95% CI
Recurrent VTE
2.1
2.3
0.89 (0.66-1.19)
Major or Clinically
Relevant Bleeding
9.4
10.0
0.93 (0.81-1.06)
Major Bleeding
1.0
1.7
0.54 (0.37-0.79
Subgroup analysis favored rivaroxaban in patients with cancer
Einstein DVT and PE
Conclusion
• Rivaroxaban in non-inferior to standard therapy with
enoxaparin/warfarin in preventing recurrent DVT/PE with
similar risk of bleeding
Caveats and Clinical Implications
• Rivaroxaban is approved for reducing recurrence of VTE
in patients with DVT/PE as an alternative to warfarin
• Offers an opportunity for easy out patient management
• Does not require monitoring
• Cost an issue
• Duration of anticoagulation unchanged
Low Dose Aspirin After Completed Course
of Anticoagulation Reduces Risk of
Recurrent VTE
ASPIRE
Brighton TA, et al. New Eng J Med 2012;367:1979-87
ASPIRE
Background
• Even after completed a traditional course of oral
anticoagulation (3-6 months), patients with a history of
unprovoked DVT have a relatively high long-term risk of
recurrent VTE (around 25% at 5 years)
Question
• Would aspirin be effective in preventing a recurrence of
VTE in patients with first episode of unprovoked VTE
who have completed a traditional course of
anticoagulation?
ASPIRE DVT
Methods
• 822 patients who completed initial
anticoagulation therapy after a first episode of
unprovoked VTE (DVT or PE)
• Randomized to aspirin 100 mg daily or placebo
• Primary Endpoint: Recurrent symptomatic VTE
• Mean Follow-Up = 37.2 months
• Results pooled with another similar previously
reported studied (WARFASA)
ASPIRE DVT - Results
ASPIRE DVT
Conclusions
• For patients with history of first unprovoked VTE, after
completion of a course of anticoagulation, use of aspirin
100 mg daily decreased the incidence of recurrent VTE
and CV events with minimal increased risk of bleeding
Caveats and Clinical Implications
• Safe, inexpensive intervention
• What about provoked DVT?
• What is the role of d-dimer and repeat duplex in
determining the duration of anticoagulation?
Warfarin Dose Assessment Every 4 Weeks
Versus Every 12 Weeks in Patients With
Stable International Normalized Ratios
Schulman S, et al. Ann Intern Med.
2011;155:653-659.
INR Testing Frequency
Background:
• Clinical guidelines differ on the optimal interval for
INR monitoring (limited data)
• A 1998 British guideline suggests that monitoring
can be done up to every 12 weeks for very stable
patients
• Underpowered Italian study stated no difference
between 4 and 6 week testing
Question: Is assessment of warfarin dosing every 12
weeks as safe as assessment every 4 weeks?
INR Testing Frequency
Methods
• 250 patients with unchanged warfarin dosing for at
least 6 months randomized to assessment at 4 week
or 12 week intervals (noninferiority trial)
• Both groups had nurse visits every 4 weeks
• Nurses following those in the 12 week group were
given sham INR results (in range) in 2 of the 3 four
week visits
• Primary Outcome = % of time in therapeutic range
• Secondary Outcome = Number of extreme INRs,
changes in maintenance dose, major bleeding
events, objectively verified thromboembolism, and
death
INR Testing Frequency - Results
The percentage of time in the therapeutic
range:
• 74.1% in the 4-week group
• 71.6% in the 12-week group
• This met the requirement for noninferiority
• Secondary outcomes:
– No difference between groups
– Fewer dosage changes, and fewer extreme
INRs that were >4.5 or <1.5 in 12 week group
INR Testing Frequency
Conclusion:
• Assessment of warfarin dosing every 12 weeks
seems to be safe and noninferior to assessment
every 4 weeks
Caveat and Clinical Implications
• This study used sham INR and had monthly RN
visits in extended follow-up group
• These results demonstrate that the frequency of
assessing warfarin dosing may be substantially
reduced in stable patients
Addition of Clopidogrel to Aspirin in
Patients with History of Lacunar Stroke
SPS 3
SPS3 Investigators. New Eng J Med 2012;367:817-825
SPS-3
Background
• Lacunar strokes are a frequent type of stroke caused by
cerebral small vessel disease and hypertension usually
• Aspirin is the standard of care post lacunar stroke
• Addition of clopidogrel to aspirin has been found to be
effective in patients with atrial fibrillation and ACS
• Combined therapy with clopidorgrel and aspirin is
associated with a greater risk of bleeding than with either
agent alone
Question
• In patients with history of lacunar infarction would the
addition of clopidogrel decrease the risk of recurrent
stroke?
SPS-3
Methods
• 3020 patients with recent symptomatic lacunar
infarction identified by MRI
• All patients on aspirin 325 mg daily
• Randomized to clopidogrel mg daily or placebo
• Primary Efficacy Endpoint = recurrent stroke
• Primary Safety Endpoint = major extracranial
hemorrhage
• Mean Follow-Up = 3.4 years
SPS-3 - Results
Recurrent Stroke Risk
Safety
1) Risk of major hemorrhage doubled with dual therapy (2.1%/yr vs 1.1%/yr)
2) Risk of death increased with dual therapy (113 deaths vs 77 deaths)
SPS-3
Conclusion
• Among patients with recent lacunar stroke, the
addition of clopidogrel to aspirin did not
significantly reduce the risk of stroke but did
increase the risk of bleeding and death
SPS3
Clinical Implications and Caveats
• Dual anti-platelet therapy should be used only in
rare instances and with caution for secondary
prevention of lacunar infarction
• Does not tell us which is the preferred antiplatelet agent in monotherapy
• Does not necessarily apply to other stroke
etiologies
• Await results of SPS-3 BP arm where patients
randomized to SBP goal <130 mmHg vs 130150 mmHg
Subclinical atrial fibrillation
and the risk of stroke
Healey JS, et al. N Engl J Med. 2012 Jan
12;366:120.
Subclinical Atrial Fibrillation
Background
• 25% of all ischemic strokes are cryptogenic, and
subclinical atrial fibrillation is suspected to be a possible
cause in many of these
• The prevalence and prognosis of subclinical atrial
fibrillation has been difficult to assess
• More than 400,000 pacemakers and ICDs implanted
each year in North America
• These have the capacity to record episodes of atrial
tachyarrhythmia
• The significance of pacemaker detected subclinical atrial
fibrillation is unknown
Subclinical Atrial Fibrillation
Question:
• In patients with pacemakers or ICDs, does the
detection of subclinical atrial tachyarrhythmia
signify an increased risk of stroke?
Subclinical Atrial Fib
Methods
• 2,580 patients with HTN who had pacemaker
(95%) or ICD (5%) placed
• Episodes of atrial rate >190 lasting at least six
minutes recorded for 1st three months 
followup for 2.5 years for ischemic stroke or
systemic embolism
Subclinical Atrial Fibrillation - Results
• By 3 months, subclinical atrial tachy had occurred in
10.1% of patients.
• Over the next 2.5 years, the risk of stroke was doubled in
these patients compared to those without atrial tachy
• Those who had episodes lasting >17.7 hours had a
higher risk of stroke (4.89% per year) than those in lower
quartiles of duration
• Risk of developing clinical atrial fibrillation also 5x higher
in those with subclinical atrial fibrillation
Subclinical Atrial Fibrillation - Results
For subclinical atrial
fibrillation:
Risk of Stroke
increased with
CHADs2 score
However, the risk was
not as great as in
studies of clinical
atrial fibrillation:
CHADS2
Score
Stroke
risk this
study
%/yr
Stroke risk
in clinical
AF study
%/yr
1
0.56
2.8
2
1.29
4.0
≥3
3.78
>6.4*
Subclinical Atrial Fibrillation
Conclusions
• Patients with asymptomatic subclinical atrial
fibrillation identified on PPM or ICD had
– Increased risk of stroke (related to CHADs2 score but
less risk than with clinical atrial fibrillation)
– Increased risk of developing clinical atrial fibrillation
Caveats:
• Does not tell us whether or not these patients
would benefit from anticoagulation
Subclinical Atrial Fibrillation
Clinical Implications:
•Patients who exhibit atrial tachy on quarterly
pacemaker reports should:
 Be followed for development of clinical atrial fibrillation
 Perhaps anticoagulation should be considered in those
with a CHADs@ score of 3 or greater or with episodes
lasting over 17 hours(hypothesis should be tested in an
RCT)
•These data could have important implications for
work-up of patients with ‘cryptogenic’ stroke
Clinical Implications of Latest Trials in
Antiplatelet and Anticoagulant Therapy
• Consider novel anticoagulants as an alternative to
warfarin in patients with DVT/PE
• Consider use of aspirin after completing recommended
course of anticoagulation in patients with DVT/PE
• Consider decreasing the frequency of INR monitoring in
patients with very stable INRs
• Avoid use of dual antiplatelet therapy in patients with
lacunar stroke
• Be aware of implications of subclinical atrial fibrillation in
patients with PPMs, ICDs, and history of cryptogenic
stroke
• Eagerly await future studies to help clarify and
strengthen these recommendations
Questions & Answers
?