New study on inferior vena cava filters

IVC filters have been troubled by very limited evidence despite advances in the technology. Recommendations are largely based on clinical rationale with wide variation among published guidelines and rampant non evidence based use.

I was alerted to a new JAMA report addressing this topic by Larry Husten at Cardiobrief (full post here). Husten makes the point that IVC filters are over utilized. While I agree with that premise his post, sensationalistically titled “No Benefit For A Commonly Used Cardiac Device,” does much to distort the general issue of IVC filter use. From the sound of the title you'd think it was time to abandon the filter altogether. But that's not at all what the JAMA study says. It addresses a specific and very limited situation (whether to add insertion of a filter to anticoagulation treatment in PE patients who also have a DVT and at least one risk factor for severity), one that accounts for relatively little IVC filter use today! Moreover a similar study (although some of its patients had DVT without PE) was published 17 years ago and had somewhat similar results. So this is hardly a game changer.

From the new study:

Objective To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence.

Design, Setting, and Participants Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers.

Interventions Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement.

Main Outcomes and Measures Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications.

Results In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients.

This study addresses a question that is seldom considered in day to day practice. On the other hand, a question that does occasionally present itself is whether to insert an IVC filter (alongside anticoagulation and/or thrombolysis) in patients critically ill with PE, particularly those in shock or requiring mechanical ventilation. Such patients were not represented in the JAMA paper. But, for such critically ill patients with PE, although not in the form of RCTs, there are compelling data to suggest that IVC filters save lives. (See here and here). This is the best information we are likely to have. A randomized trial will not be done any time soon and maybe not at all, for logistical reasons and lack of equipoise.

What about other indications for an IVC filter? The universally accepted indication, and the only one recognized by the most strictly evidence based guideline, that of the Thrombosis Interest Group of Canada, is the presence of acute DVT in the face of an absolute contraindication to anticoagulation. The more liberal ACCP guidelines also recommend filter insertion in patients with PE, with or without DVT, in the face of an absolute anticoagulation contraindication.

Perioperative management of patients taking target specific oral anticoagulants

Although the target specific oral anticoagulants (TSOAC) have been validated in clinical trials and approved for several years in the U.S., high level data regarding certain aspects of their use are lacking.  As a result, clinicians have had to look to low level reports, expert opinion and pharmacokinetic information for guidance in situations such as bleeding and perioperative management.  Because the experience has grown and opinions change this has been a moving and controversial target.  Keeping up with continuously evolving recommendations has been a challenge.  Thus it is appropriate to revisit the topic of perioperative management. 

Key issues are:

How long to hold the drug before non-emergent surgery

How soon to restart the drug after surgery

How to assess for drug activity via laboratory testing

How to deal with bleeding




This post draws from two reviews, one published in the NEJM in 2013 and another just published review in Critical Care Forum.  Recommendations differ slightly between the two reviews.  Although the CCF article is more recent there's no reason to say one is better than the other since no high quality evidence came out during the interval.


How long to stop the drug before non-emergent surgery

NEJM review recommendations---

Dabigatran:  For creatinine clearance 50 and above 1-2 d;  for clearance below 50 3-5 d.  Consider holding longer for procedures deemed to be at high risk.

Rivaroxaban:  For normal clearance at least 1 day; for clearance of 60-90, 2 d; 30-59, 3 d; 15-29, 4 d.  Consider holding longer in high bleeding risk procedures.

Apixaban:  For clearance over 60, 1-2 d; 50-59, 3 d; 30-49, 5 d.  In this case a distinction between high and low bleeding risk procedures was not made, but the authors of the NEJM review vaguely suggest allowing more time in high risk procedures.  (In fact the NEJM authors make a blanket statement for all three drugs, regardless of procedure bleeding risk, to allow more time than the above statements recommend).

Note that the recommendations for the three drugs are inconsistent in their wording and categorization.  That's because they are derived largely from product labeling which is subject to various quirks in FDA approval terms and conditions for the respective drugs.


CCF review recommendations---

Dabigatran:  For clearance of 80 or above at least 24 hrs for low bleeding risk procedures and 48-72 hrs for high risk;  50-80, at least 36 hrs for low risk, at least 72-96 hrs for high;  30-50, at least 48 and 96 hs respectively.  If concomitant interacting drugs (anti-platelet agents, amiodarone) add 12 hrs.

Rivaroxaban and Apixaban (no distinction made, in contrast to the NEJM article):  Clearance of 80 or above, at least 24 hrs for low risk, at least 48 hrs for high;  50-80, at least 24 hrs for low, at least 48-72 hrs for high;  30-50, at least 24 hrs for low, at least 72-96 hrs for high; 16-30, at least 36 hrs for low, at least 96 hrs for high.  Add 12 hrs for the presence of interacting drugs (same drugs as for dabigatran). 



When to restart post op

No distinction among the three drugs applies to this recommendation.

From NEJM---no recommendation concerning low risk procedures; at least 48 hrs for high risk.

From CCF---6-8 hrs for low risk, 48-72 hrs for high risk.


Laboratory testing to assess residual drug effect

From NEJM---

Dabigatran:  aPTT  (normal value may rule out significant residual effect).

Rivaroxaban:  PT or anti-Xa  (normal values may rule out significant residual effect).

Apixaban:  Anti-Xa.

Differences in the recommendation for the latter two drugs, which are in the same class, may reflect labeling quirks rather than real biologic difference.


From CCF---

Dabigatran:  Thrombin time (Haemoclot).

The other two:  anti-Xa

Note:  Having blogged this topic extensively I can tell you that the recommendations on laboratory testing for drug effect are extremely variable.  Despite the convenience of the PT and PTT their use for this purpose is controversial.  On the other hand TT and anti-Xa assays are not readily available in many hospitals. 



How to deal with bleeding

From NEJM---

Dabigatran:  Consider factor VIII inhibitor bypass activity (FIBA), VIIa, and/or hemodialysis.

Rivaroxaban:  Consider PCC.

Apixaban:  Consider PCC or charcoal hemoperfusion.


From CCF---

No distinction made among the drugs.  For all, consider PCC or FIBA.  Dialysis is mentioned as a possible remedy in the body of the paper for dabigatran but not included in the final recommendations.

Anti-NMDA-receptor encephalitis

A great overview at Academic Life in Emergency Medicine.

Trends in pre-hospital oxygen administration for chest pain patients

From a recent study:

Objectives. The purpose of this study was to examine trends in oxygen administration following the 2010 American Heart Association guidelines recommendation to withhold oxygen therapy for patients with uncomplicated presentations of ACS whose SpO2 is 94% or higher...

Results. 10,552 patient encounters by 2,447 paramedic students from 195 paramedic programs representing 49 states were included for analysis. Prior to release of the new guidelines (2010), 71.9% (95% CI 69.8–74.0%) of patients with SpO2 greater then or equal to 94% received supplemental O2. Rates of O2 administration were significantly lower in 2011 (64%; 95% CI 62.7–65.3%) and in 2012 (53.1%; 95% CI 51.5–54.7). The odds of a hemodynamically stable chest pain patient with SpO2 greater than or equal to 94% receiving supplemental oxygen in 2011 were 1.4 times lower compared to patients in 2010 (95% CI 1.3–1.6). Similarly, the odds of patients in 2012 receiving supplemental oxygen were 2.3 times lower compared to patients in 2010 (95% CI 2.0–2.6). The odds of receiving supplemental oxygen decreased by 4% for each 1% increase in SpO2 beyond the 94% threshold (OR = 0.96; 95% CI 0.94–0.98). Conclusions. The prehospital administration of supplemental O2 decreased significantly following release of the 2010 updated guidelines; however, our data revealed that 50% of patients not meeting criteria for administration still received supplemental O2.

Proton pump inhibitors coadministered with dual antiplatelet therapy: the controversy continues

From a recent systematic review:

Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole.

Conclusions—Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non–ST-segment–elevation myocardial infarction treated with DAPT are warranted.

Aspirin lowers mortality in patients with community acquired pneumonia

From a recently published study:

Methods and Results Consecutive patients admitted to the University‐Hospital Policlinico Umberto I (Rome, Italy) with community‐onset pneumonia were recruited and prospectively followed up until discharge or death...

One thousand and five patients (age, 74.7±15.1 years) were included in the study: 390 were receiving aspirin (100 mg/day) at the time of hospitalization, whereas 615 patients were aspirin free. During the follow‐up, 16.2% of patients died; among these, 19 (4.9%) were aspirin users and 144 (23.4%; P less than 0.001) were aspirin nonusers. Overall, nonfatal CVEs occurred in 7% of patients, 8.3% in nonaspirin users, and 4.9% in aspirin users (odds ratio, 1.77; 95% confidence interval, 1.03 to 3.04; P=0.040). The Cox regression analysis showed that pneumonia severity index (PSI), severe sepsis, pleural effusion, and PaO2/FiO2 ratio less than 300 negatively influenced survival, whereas aspirin therapy was associated with improved survival. Compared to patients receiving aspirin, the propensity score adjusted analysis confirmed that patients not taking aspirin had a hazard ratio of 2.07 (1.08 to 3.98; P=0.029) for total mortality.

Conclusions This study shows that chronic aspirin use is associated with lower mortality rate within 30 days after hospital admission in a large cohort of patients with pneumonia.

This is astounding and far more robust than any of today's core measures or care pathway components. This is yet another reason core measures are ineffective: they are hopelessly out of date. Remember, this finding is not new. Based on an older study I suggested, almost two years ago, that aspirin administration be part of the pneumonia order set.

Are face-to-face handoffs really necessary?

This question was examined in a recent study of hospitalized patients:

OBJECTIVE

Examine the relationship between face-to-face handoffs and the rate of patient outcomes, including adverse events.

DESIGN

Retrospective cohort.

SETTING

A 1157-bed academic tertiary referral hospital.

PATIENTS

There were 805 adult patients admitted to general internal medicine services.

INTERVENTION

Retrospective comparison of clinical outcomes, including the rate of adverse events, of patients whose care was transitioned with and without face-to-face handoffs.

MEASUREMENTS

Rapid response team calls, code team calls, transfers to a higher level of care, death in hospital, 30-day readmission rate, length of stay, and adverse events (as identified using the Global Trigger Tool).

RESULTS

There was no significant difference with respect to the frequency of rapid response team calls, code team calls, transfers to a higher level of care, deaths in hospital, length of stay, 30-day readmission rate, or adverse events between patients whose care was transitioned with or without a face-to-face handoff.

From comments on this study in ACPHospitalist Weekly:

However, they speculated that the lack of effect with face-to-face handoffs could suggest that clinicians were more vigilant in gathering data when they didn't receive a face-to-face handoff, spending more time reviewing the medical record, speaking with the patients, and communicating with other clinicians.

The results suggest that, as long as key information is communicated by other means (such as electronic tools, email, or phone), a face-to-face handoff is "not vital to ensure a safe care transition," the authors wrote. Future investigations should look for other strategies or qualities that affect the safety of handoffs, they suggested.

Cost comparisons in ACS for PCI and non-PCI capable hospitals

From a recent analysis:

Conclusions—Despite higher PCI and coronary artery bypass graft rates for Medicare patients initially presenting to PCI hospitals, PCI hospitals were only $627 costlier than non-PCI hospitals for the treatment of patients with acute myocardial infarction in 2008.

Outpatient treatment of PE: what does the evidence tell us?

From a Cochrane Database systematic review:

SEARCH METHODS:

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched October 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 9). The TSC also searched clinical trials databases. The review authors searched LILACS (last searched November 2014).

SELECTION CRITERIA:

Randomized controlled trials of outpatient versus inpatient treatment in people diagnosed with acute PE...

MAIN RESULTS:

We included one study, involving 339 participants. We ranked the quality of the evidence as very low due to not blinding the outcome assessors, the small number of events with imprecision in the confidential interval (CI), the small sample size and it was not possible to verify publication bias. For all outcomes, the CIs were wide and included clinically significant treatment effects in both directions: short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30) and 90 days (RR 6.88, 95% CI 0.36 to 134.14, P = 0.20), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51) and participant satisfaction (RR 0.97, 95% CI 0.92 to 1.03, P = 0.30). PE-related mortality, minor bleeding, and adverse course such as hemodynamic instability and compliance were not assessed by the single included study.

AUTHORS' CONCLUSIONS:

Current very low quality evidence from one published randomized controlled trial did not provide sufficient evidence to assess the efficacy and safety of outpatient versus inpatient treatment for acute PE in overall mortality, bleeding and recurrence of PE adequately. Further well-conducted research is required before informed practice decisions can be made.

Now that target specific oral anticoagulants are approved for PE treatment this becomes an important question. If good quality RTC evidence is unavailable we do have other types of evidence that address the problem, specifically evidence showing that, using biomarkers, echocardiography and clinical criteria we can predict patients whose sort term risk is very low. Is that type of evidence enough? Do we even need RCT evidence?

Via Hospital Medicine Virtual Journal Club.

Saddle pulmonary embolism and knee jerk alarm

Here's an interesting paper linked at Hospital Medicine Virtual Journal Club. From the abstract:

Saddle pulmonary embolism (PE) is defined as the presence of a visible thromboembolus that straddles the bifurcation of the main pulmonary artery. It occurs in about 2-5% of all PE cases [1]. Visualization of saddle PE on a Computed Tomography (CT) scan causes alarm among physicians due to the possibility of a large clot burden and impending hemodynamic collapse. However, recent studies have challenged this reflexive assumption, along with the assumption that clot burden predicts outcomes [2].

Not that saddle PE isn't serious, but all too often the appearance of a “saddle” trumps further thinking about parameters that mean more such as the shock index, biomarkers and echocardiographic assessment of RV function.

New oral anticoagulants for heparin induced thrombocytopenia (HIT)

Low level evidence suggests they may provide an alternative:

MATERIALS AND METHODS:

We retrospectively identified 22 patients with HIT who were treated by our group with a combination of NOAC and a short course of argatroban. These patients were evaluated in a prospective fashion for development of outcomes at a mean follow up of 19±3months.

RESULTS:

There were a total of 5 deep and 2 superficial vein thromboses diagnosed at index hospitalization. No patient developed arterial thrombosis. All patients tolerated NOAC and their platelet count normalized before discharge. At 19months of follow-up, 6 patients had died of non-thrombotic causes. There was no bleeding, limb loss or recurrent venous thromboembolism in any patient.

CONCLUSIONS:

In patients with HIT, a short course of parenteral treatment with argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. Development of HIT however, portends a poor prognosis independent of vascular thrombosis.

Via Hospital Medicine Virtual Journal Club.

Neurologic prognosis after cardiac arrest: a statement from the European Resuscitation Council and the European Society of Intensive Care Medicine

An evidence based approach to the evaluation of coma post cardiac arrest and an essential reference for hospitalists.

Mucormycosis

This post from Emergency Medicine Ireland has a link to a full text review which should be read in its entirety. I have posted previously on the subject here and here.

Update on serious MRSA infections

From Current Opinion in Infectious Diseases:

Recent findings  Elevations in the vancomycin minimum inhibitory concentration within the susceptible range are associated with treatment failure and mortality in the treatment of MRSA infections. Ceftaroline and ceftobiprole are anti-MRSA cephalosporins and are noninferior to comparator agents in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and pneumonia. Tedizolid is more potent than linezolid, has improved pharmacokinetics and reduced toxicity and is active against cfr-containing S. aureus. Telavancin now has approval for treatment of hospital-acquired pneumonia, and recent phase 2 trial data showed similar cure rates in S. aureus bacteremia. Dalbavancin and oritavancin are administered once weekly and are noninferior to comparators for acute bacterial skin and skin structure infections. Resistance has emerged against many new anti-MRSA antimicrobials including ceftaroline. Combination therapy of β-lactams with vancomycin or daptomycin is increasing.

Summary  Several new MRSA-active agents are now approved for use, although much of the data is derived from treatment of acute bacterial skin and skin structure infections or pneumonia. Further studies are required for more invasive infections, such as bacteremia and endocarditis.

MRSA pneumonia: what's the best treatment?

Is it vancomycin or linezolid? The evidence is mixed and the controversy continues but according to this review linezolid seems to be gaining the edge.

Via Hospital Medicine Virtual Journal Club.

Procalcitonin as a prognostic indicator in sepsis

From BMC Research Notes:

Background

Procalcitonin is useful for the diagnosis of sepsis but its prognostic value regarding mortality is unclear. This prospective observational study was designed to study the prognostic value of procalcitonin in prediction of 28 day mortality in patients of sepsis. Fifty-four consecutive patients of sepsis, severe sepsis and septic shock defined using the 2001 Consensus Conference SCCM/ESICM/ACCP/ATS/SIS criteria from medical Intensive Care Unit (ICU) of a tertiary care center in New Delhi, India were enrolled from July 2011 to June 2013. Procalcitonin (PCT), C-reactive protein (CRP) measurements were recorded on day 1, day 7 and day 28 of follow up.

Results

Procalcitonin value was a better predictor of all-cause short-term mortality than C-reactive protein. Those patients with Procalcitonin levels less than 7 ng/ml showed higher cumulative survival than those with level [greater than or equal to]7 ng/ml (69.1% vs. 39.5%, p = 0.02). No such effect was observed in relation to C-reactive protein. Procalcitonin levels [greater than or equal to]7 ng/ml predicted mortality with a hazard ratio of 2.6(1.1-6.3).

Conclusions

A Procalcitonin value [greater than or equal to]7 ng/ml obtained at the time of admission to the ICU is a predictor of short-term mortality and thus may allow the identification of those septic patients at increased mortality risk, and help improve their treatment.

Median procalcitonin levels for survivors and non survivors are presented here.

Also of note from the study:

Procalcitonin levels were also significantly higher in patients with septic shock as compared to that with severe sepsis (34.6 ± 36.7 vs. 15.0 ± 29.9 ng/mL; p = 0.03) and sepsis (34.6 ± 36.7 vs. 3.8 ± 1.6 ng/mL; p = 0.008) (Figure 3).

Via Hospital Medicine Virtual Journal Club.

Initial arrest rhythm to drive post resuscitation care decisions

Here are the findings from an interesting study published in Resuscitation:

Aim

We investigated the impact of intensified postresuscitation treatment in comatose survivors of out-of-hospital cardiac arrest (OHCA) of presumed cardiac etiology according to the initial rhythm at the emergency medical team arrival.

Methods

Interventions and survival with Cerebral Performance Category (CPC) 1–2 within each group were retrospectively compared between the periods of conservative (1995–2003) and intensified (2004–2012) postresuscitation treatment.

Results

In shockable group, therapeutic hypothermia (TH) increased from 1 to 93%, immediate invasive coronary strategy from 28 to 78%, intraaortic balloon pump from 4 to 21%, vasopressors/inotropes from 47 to 81% and antimicrobial agents from 65 to 86% during the intensified period as compared to conservative period (p less than 0.001). This was associated with increased survival with CPC 1–2 from 27 to 47% (p less than 0.001). After adjusting for age, sex and prehospital confounders, TH (OR = 2.12, 95% CI 1.25–3.61), percutaneous coronary intervention (OR 1.77, 95% CI 1.15–2.73) and antimicrobial agents (OR = 12.21, 95% CI 5.13–29.08) remained associated with survival with CPC 1–2. In non-shockable patients, TH also significantly increased from 1 to 74%, immediate invasive coronary strategy from 8 to 51%, intraaortic balloon pump from 2 to 9% and vasopressors/inotropes from 56 to 84% during intensified period without concomitant increase in survival with CPC 1–2 (7% vs. 9%; p = 0.27). After adjustment, only antimicrobial agents (OR = 8.43, 95% CI: 1.05–67.72) remained associated with survival with CPC 1–2.

Of particular interest is the frequency with which antibiotics were given and the degree to which their use was associated with better survival.

Karl B. Kern MD, in a related editorial, made the following points:

In contrast to the referenced study, findings form a large database in Arizona showed benefit from a similar intensified post-arrest care bundle regardless of the presenting rhythm. (In the referenced study only antibiotics were associated with better outcomes across all rhythm groups).

Overdiagnosis and treatment of pulmonary embolism: the emperor still has no clothes

That fairy tail reference, of course, is to the famous Annals article way back in 1977. Some 38 years later we still may be overdiagnosing and overtreating PEs, but for different reasons. That is the subject of a great post overat EP Monthly. It focuses on 1) the knee jerk overuse of CTA in patients with chest symptoms (failure to apply clinical prediction rules such as the Wells score) and 2) the frequent finding, with the current heavy use of CTA, of questionable isolated small filling defects that may not need to be treated, or may not represent PE at all. It's a great read and well referenced. In reading the post, keep in mind the following:

It is not known whether such low clot burden PEs need to be treated at all. Investigators believe there is clinical equipoise and so a randomized clinical trial is now ongoing to answer the question.

Many such low burden filling defects picked up on CT would be “missed” with perfusion lung scanning. However, perfusion lung scanning is at least as sensitive (with normal perfusion or when very low probability criteria are met) as CT for clinically significant emboli and in terms of outcomes.

Despite the reported incidence of PE going way up over the years since the introduction of CT motality for PE has not changed, indirect evidence that the small lesions picked up on CT are clinically insignificant and should not be treated.

The use of CTA in preference to VQ scanning is popularity based and not evidence based. There is no evidence that CT is superior to nuclear scanning as the initial imaging modality.

Cardiovascular consequences of hypoglycemia in diabetes treatment: an emerging threat

From a recent review:

Hypoglycemia in people with diabetes mellitus (DM) has been potentially linked to cardiovascular morbidity and mortality. Pathophysiologically, hypoglycemia triggers activation of the sympathoadrenal system, leading to an increase in counter-regulatory hormones and, consequently, increased myocardial workload and oxygen demand. Additionally, hypoglycemia triggers proinflammatory and hematologic changes that provide the substrate for possible myocardial ischemia in the already-diseased diabetic cardiovascular system. Hypoglycemia creates electrophysiologic alterations causing P-R–interval shortening, ST-segment depression, T-wave flattening, reduction of T-wave area, and QTc-interval prolongation. Patients who experience hypoglycemia are at an increased risk of silent ischemia as well as QTc prolongation and consequent arrhythmias.

FDA approval of ivabradine for heart failure

Via Cardiobrief:

The FDA on Wednesday approved ivabradine (Corlanor), Amgen’s new heart failure drug. The drug has been available for several years in Europe, where it is sold by Servier under the brand names of Corlentor and Procoralan.

Ivabradine was approved for the reduction of hospitalization from worsening heart failure. It is indicated for use in stable heart failure patients who are in sinus rhythm, have a resting heart rate of at least 70 bpm, and who are also taking the highest tolerable dose of a beta blocker. Ivabradine slows the rate of the heart by inhibiting the so-called “funny” current within the heart’s natural pacemaker, the sinoatrial node.

The funny current is an inward cation flux which helps initiate diastolic depolarization in pacemaker cells. So, if you inhibit the funny current heart rate slows. I have seen the FDA press release for consumers but not the product labeling. From the press release:

Corlanor is approved for use in certain people who have long-lasting (chronic) heart failure caused by the lower-left part of their heart not contracting well. The drug is indicated for patients who have symptoms of heart failure that are stable, a normal heartbeat with a resting heart rate of at least 70 beats per minute and are also taking beta blockers at the highest dose they can tolerate.

Reading between the lines it would appear that the drug is approved for patients with systolic dysfuction. The proviso concerning beta blockers, it would seem to me, will restrict the use of the drug, since many patients at the limits of beta blocker tolerance are there due to low heart rate. The niche for ivabradine may be in those patients at the limits of beta blocker tolerance for blood pressure reasons who still have a heart rate of at least 70.

An often forgotten fact is that heart rate reduction by itself is good for patients with heart failure. That was the premise of the the SHIFT study, the results of which are the basis of the drug's approval. From the Lancet paper:

Background

Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population...

Findings

In the placebo group, patients with the highest heart rates (greater than or equal to 87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to less than 72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95% CI 1·84–2·98, p less than 0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3–19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85–1·06, p=0·352).

Interpretation

Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure.