Month: February 2018

Week 34 – PLATO

“Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”

by The Study of Platelet Inhibition and Patient Outcomes (PLATO) investigators

N Engl J Med. 2009 Sep 10;361(11):1045-57. [free full text]
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In patients with acute coronary syndrome (ACS), with or without ST-segment elevation, clinical practice guidelines recommend dual antiplatelet therapy with aspirin plus one of either clopidogrel, prasugrel, or ticagrelor to reduce risk of thrombosis. The 2009 PLATO trial was designed to determine whether ticagrelor was superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS as well as whether this potential benefit came with an increased risk of major bleeding events.

Population:
Patients hospitalized for ACS with or without ST-elevations with symptom onset during the previous 24 hours.

If there were no ST-elevations, patients were required to have at least 2 of 3 of the following: ST change reflecting ischemia, elevated cardiac biomarkers (i.e. troponin), or one of several risk factors (age ≥ 60, prior MI/CABG, CAD w/ ≥ 50% stenosis in ≥ 2 vessels, prior ischemic stroke/TIA/carotid stenosis ≥ 50%, DM, PAD, CrCl < 60)

Intervention: ticagrelor 180mg loading dose followed by 90mg BID + aspirin

Comparison: clopidogrel 300mg loading dose followed by 75mg daily + aspirin

Outcomes:
Primary: composite of death from vascular causes, MI, or CVA

Secondary

  • major bleeding (fatal bleeding, intracranial bleeding, intrapericardial bleeding w/ tamponade, hemorrhagic shock, decline of Hgb < 5.0, or requiring transfusion of 4 units pRBC)
  • all-cause mortality, MI, or stroke
  • composite of death from vascular mortality, MI, stroke, recurrent severe ischemia, recurrent ischemia, TIA, or other arterial thrombotic event
  • stent thrombosis

 

Results:
18,624 patients from 862 centers in 43 countries were recruited and enrolled in the study. 9,333 were randomized to the ticagrelor group, and 9291 were randomized to the clopidogrel group. Patients were followed for up to 12 months.

The two treatment groups did not statistically differ in baseline characteristics, non-study medications following randomization, or procedures following randomization. Both groups started the study drug at a median of 11.3 hours after the onset of chest pain.

The primary end point (death from vascular causes, MI, or CVA) occurred less often in the ticagrelor group than in the clopidogrel group – 9.8% vs 11.7% (HR 0.77 – 0.92; p < 0.001; NNT = 52.6).

The groups did not significantly differ in terms of major bleeding – 11.6% vs. 11.2% (HR 1.04; 95% CI 0.95 – 1.13; p = 0.43).

Patients who received ticagrelor trended toward an increased rate of intracranial bleeding (26 [0.3%] vs. 14 [0.2%], p = 0.06), including a statistically significant increase in fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%], p = 0.02) as well as non-CABG bleeding (4.5% vs. 3.8%, p = 0.03). However, there were fewer episodes of other types of fatal bleeding in the ticagrelor group.

Regarding other secondary outcomes, ticagrelor performed better in:

  • composite of all-cause, MI, or stroke – 10.2% vs. 12.3% (HR 0.84; 95% CI 0.77 – 0.92; p < 0.001; NNT 47.6)
  • composite of death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event – 14.6% vs. 16.7% (HR 0.88; 95% CI 0.81 – 0.95; p < 0.001; NNT 47.6)
  • stent thrombosis – 1.3% vs. 1.9% (HR 0.67; 95% CI 0.50-0.91; p = 0.009, NNT = 167).

Dyspnea was more common in the ticagrelor group than in the clopidogrel group (13.8% vs 7.8%, p < 0.001). There was a higher incidence of ventricular pauses in the first week in the ticagrelor group relative to the clopidogrel group; however, the two groups did not differ in incidence of syncope or pacemaker implantation. Discontinuation of study drug due to adverse event was more common in the ticagrelor group (7.4% vs. 6.0%). Ticagrelor was also associated with elevations in uric acid and creatinine.

Implication/Discussion:
PLATO demonstrated that treatment of ACS with ticagrelor (vs. clopidogrel) significantly reduced the rate of death from vascular causes, MI, or stroke, without increasing the risk of major bleeding.

 Although ticagrelor patients did demonstrate higher rates of intracranial and non-CABG bleeding, this bleeding did not qualify as “major bleeding.” They also complained more frequently of dyspnea (a known adverse effect of the drug). Discontinuation of ticagrelor due to dyspnea occurred in 0.9% of patients. Due to this risk of dyspnea, as well as the risk of elevated serum uric acid and creatinine, caution should be used in those with a history of COPD, asthma, CHF, gout, and CKD who are considering using ticagrelor.

Strengths of this study include that it was a double-blind, randomized controlled trial with a large patient population. Weaknesses include that the study was funded by AstraZeneca, manufacturers of Brilinta (the brand name of ticagrelor). Also, the study drug did not perform as well in North American sites or underweight patients, yet the authors do not offer clear explanations as to why.

Bottom line:
Patients with a high risk of thrombosis and a low risk of bleeding may benefit most from ticagrelor. Ticagrelor has a mortality benefit when compared to clopidogrel. But ticagrelor should be used with caution in those with pulmonary disease (e.g. COPD or asthma), CKD, and heart block (due to association with ventricular pauses).

Drug cost: At time of study. Ticagrelor: $108/month; Clopidogrel: $26/month


Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Long-term antiplatelet therapy after coronary artery stenting in stable patients”
4. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease

Summary by Patrick Miller, MD

Week 33 – CHOIR

“Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease”

by the Investigators in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)

N Engl J Med. 2006 Nov 16;355(20):2085-98. [free full text]
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Anemia is a highly prevalent condition in CKD and ESRD. The anemia is largely attributable to the loss of erythropoietin production due to the destruction of kidney parenchyma. Thus erythropoiesis-stimulating agents (ESAs) were introduced to improve this condition. Retrospective data and small interventional trials suggested that treatment to higher hemoglobin goals (such as > 12g/dL) was associated with improved cardiovascular outcomes. However, a prospective trial in ESRD patients on HD with a hemocrit treatment target of 42% vs. 30% demonstrated a trend toward increased rates of non-fatal MI and death in the higher-target group. In an effort to clarify the hemoglobin goal in CKD patients, the 2006 CHOIR trial was designed. It was hypothesized that treatment of anemia in CKD to a target of 13.5g/dL would lead to fewer cardiac events and reduced mortality when compared to a target of 11.3g/dL.

Population: adults with CKD (eGFR 15-50ml/min) and Hgb < 11.0 g/dL

Notable exclusion criteria: active cancer, prior therapy with epo.

Patients who developed a requirement for dialysis were terminated from the study.

Intervention: target hemoglobin 13.5 g/dL with a regimen of epo support

Comparison: target hemoglobin 11.3 g/dL with a regimen of epo support

Outcome:

Primary – composite of death, MI, hospitalization for CHF, or stroke

Secondary:

  • each of the four components of the composite primary endpoint
  • need for renal replacement therapy
  • hospitalization for any cause
  • quality of life as measured by the Linear Analogue Self-Assessment (LASA), Kidney Disease Questionnaire (KDQ), and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36)

 

Results:
This study was terminated early due to an interim analysis revealing a < 5% chance that there would be a demonstrated benefit for the high-hemoglobin group by the scheduled end of the study.

Results from 715 high-hemoglobin and 717 low-hemoglobin patients were analyzed.

Baseline characteristics were similar among the two groups aside from for higher rates of HTN (p=0.03) and CABG (p=0.05) in the high-hemoglobin group. Rates of iron supplementation during the study were similar among the two groups (~50%).

The mean change in hemoglobin was +2.5 g/dL in the high-hemoglobin group versus +1.2g/dL in the low-hemoglobin group (p<0.001).

The primary endpoint occurred in 125 of the high-hemoglobin patients (17.5%) versus 97 of the low-hemoglobin patients (13.5%) [HR 1.34, 95% CI 1.03-1.74, p=0.03; number needed to harm = 25].

There were no significant group differences among the four components of the primary endpoint when analyzed as individual secondary outcomes. Rates of renal replacement therapy (thus requiring termination from the study protocol) were 21.7% in the high-hemoglobin group versus 18.7% in the low-hemoglobin group (p=0.15). Any-cause hospitalization rates were 51.6% in the high-hemoglobin group versus 46.6% in the low-hemoglobin group (p=0.03).

Quality-of-life scores were assessed by the LASA, KDQ, and SF-36. Both groups demonstrated similar, statistically significant improvements from their respective baseline values, with the exception of a higher improvement in the emotional subset of SF-36 within the low-hemoglobin group.

The mean weekly dose of epoetin alfa required to maintain the target hemoglobin was 11,215 units/week in the high-hemoglobin group versus 6.276 units/week in the low-hemoglobin group.


Implication/Discussion:
In patients with anemia and CKD, treatment to a higher hemoglobin goal of 13.5g/dL was associated with an increased incidence of a composite endpoint of death, MI, hospitalization for CHF, or stroke relative to a treatment goal of 11.3g/dL. The higher treatment goal also led to higher utilization of epoetin alfa. There were no differences between the two groups in hospitalization rates or progression to renal replacement therapy, and the improvement in quality of life was similar among the two treatment groups.

Thus this study demonstrated no additional benefit and some harm with the higher treatment goal.

The authors note that “this study did not provide a mechanistic explanation for the poorer outcome with the use of a high target hemoglobin level.”

Limitations of this trial included its non-blinded nature and relatively high patient withdrawal rates.

Following this trial, the KDOQI guidelines for the management of anemia in CKD were changed to state that “in dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL.”

Expert opinion at UpToDate recommends administration of ESAs in iron-replete CKD and ESRD patients with Hgb < 10 g/dL with the goal of maintaining Hgb between 10 and 11.5 g/dL. Treatment should be individualized in patients with concurrent malignancy.


Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target
4. Pfeffer et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” N Engl J Med. 2009;361(21):2019.
5. UpToDate, “Treatment of anemia in nondialysis chronic kidney disease”
6. UpToDate, “Treatment of anemia in hemodialysis patients”

Summary by Duncan F. Moore, MD

Week 32 – Rifaximin Treatment in Hepatic Encephalopathy

“Rifaximin Treatment in Hepatic Encephalopathy”

N Engl J Med. 2010 Mar25;362(12):1071-81. [free full text]
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As we are well aware at Georgetown, hepatic encephalopathy (HE) is highly prevalent among patients with cirrhosis, and admissions for recurrent HE place a significant burden on the medical system. The authors of this study note that HE is thought to result from “the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.” Lactulose is considered the standard of care for the prevention of HE. It is thought to decrease the absorption of ammonia in the gut lumen through its cathartic effects and by alteration of colonic pH. The minimally absorbable oral antibiotic rifaximin is thought to further reduce ammonia production through direct antibacterial effects within the gut lumen. Thus the authors of this pivotal 2010 study sought to determine the additive effect of daily rifaximin prophylaxis in the prevention of HE.

Population: adults with cirrhosis and 2+ episodes of overt HE during the past 6 months

Notable exclusion criteria: West Haven Criteria score of 2+ at enrollment, MELD score > 25, baseline Cr > 2.0, or if prior qualifying HE episodes were 2/2 GIB, medication effect, or renal failure

Intervention: rifaximin 550mg PO BID x6 months

Comparison: placebo 550mg PO BID x6 months

Outcomes:

Primary: time to first breakthrough episode of HE (West Haven Score of 2+ or West Haven Score 0 –> 1 with worsening asterixis)
Secondary

  • time to first hospitalization involving HE
  • adverse events, including those “possibly related to infection”

Results:
299 patients were randomized. 140 and 159 patients were assigned to rifaximin and placebo, respectively. Baseline characteristics were similar among the two groups. Lactulose use prior to and during the study was similar in both groups at approximately 91%.

Breakthrough HE occurred in 31 (22.1%) of the rifaximin patients and 73 (45.9%) of the placebo patients [HR 0.42, 95% CI 0.28-0.64, p<0.001, absolute risk reduction 23.7%, NNT = 4.2]. This result was consistent within all tested subgroups, except patients with MELD score 19-24 and patients who were not using lactulose at baseline (see Figure 3).

Hospitalization involving HE occurred in 19 (13.6%) of the rifaximin patients and 36 (22.6%) of the placebo patients [HR 0.50, 95% CI 0.29-0.87, p = 0.01, absolute risk reduction 9.1%, NNT = 11.0].

There were no differences in adverse events among the two treatment groups.

Implication/Discussion:
Prophylactic rifaximin reduced the incidence of recurrent hepatic encephalopathy and its resultant hospitalizations.

This landmark trial showed a clear treatment benefit with implied savings in healthcare utilization costs associated with HE recurrences and hospitalizations. This marked effect was demonstrated even in the setting of relatively good (91%) lactulose adherence in both treatment arms prior to and throughout the trial.

On the day this trial was published in 2010, the FDA approved rifaximin for “reduction in risk of overt hepatic encephalopathy recurrence” in adults.

Because rifaximin is not generic and remains quite expensive, its financial utility is limited from an insurance company’s perspective. There is no other comparable nonabsorbable antibiotic for this indication.

UpToDate suggests starting with lactulose therapy and then adding a nonabsorbable antibiotic, such as rifaximin, both for the treatment of overt hepatic encephalopathy and for the prevention of recurrent hepatic encephalopathy. In practice, most insurance companies will require a prior authorization for outpatient rifaximin treatment, but in my recent experience this process has been perfunctory and easy.

Further Reading/References:
1. ClinicalTrials.gov, NCT00298038
2. FDA, NDA approval letter for Xifaxan (rifaximin)

Summary by Duncan F. Moore, MD

Week 31 – Symptom-Triggered Benzodiazepines in Alcohol Withdrawal

“Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal”

Arch Intern Med. 2002 May 27;162(10):1117-21. [free full text]
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Treatment of alcohol withdrawal with benzodiazepines has been the standard of care for decades. However, in the 1990s, benzodiazepine therapy for alcohol withdrawal was generally given via fixed doses. In 1994, a double-blind RCT by Saitz et al. demonstrated that symptom-triggered therapy based on responses to the CIWA-Ar scale reduced treatment duration and the amount of benzodiazepine used relative to a fixed-schedule regimen. This trial had little immediate impact in the treatment of alcohol withdrawal. The authors of this 2002 double-blind RCT sought to confirm the findings from 1994 in a larger population that did not exclude patients with a history of seizures or severe alcohol withdrawal.

Population: consecutive patients admitted to the inpatient alcohol treatment units at two European universities

Notable exclusion criteria: “major cognitive, psychiatric, or medical comorbidity”

Intervention: placebo (30mg q6hrs x4, followed by 15mg q6hrs x8), with additional oxazepam 15mg for CIWA score 8-15 and 30mg for CIWA score > 15

Comparison: scheduled oxazepam (30mg q6hrs x4, followed by 15mg q6hrs x8), with additional oxazepam 15mg for CIWA score 8-15 and 30mg for CIWA score > 15

Outcomes:

Primary

  • cumulative oxazepam dose at 72hrs
  • oxazepam treatment duration

Secondary

  • incidence of seizures, hallucinations, and delirium tremens at 72hrs
  • subjective scales of “health concerns,” anxiety, depression, energy level, physical functioning, and vitality over the preceding 3 days, assessed at 72hrs

Subgroup analysis: exclusion of symptomatic patients who did not require any oxazepam

Results:
117 patients completed the trial. 56 had been randomized to the symptom-triggered group, and 61 had been randomized to the fixed-schedule group. The groups were similar in all baseline characteristics except that the fixed-schedule group had on average a 5-hour longer interval since last drink prior to admission. Only 39% of the symptom-triggered group actually received oxazepam, while 100% of the fixed-schedule group did (p < 0.001).

Patients in the symptom-triggered group received a mean cumulative dose of 37.5mg versus 231.4mg in the fixed-schedule group (p < 0.001). The mean duration of oxazepam treatment was 20.0 hours in the symptom-triggered group versus 62.7 hours in the fixed-schedule group.

The group difference in total oxazepam dose persisted even when patients who did not receive any oxazepam were excluded. Among patients who did receive oxazepam, patients in the symptom-triggered group received 95.4 ± 107.7mg versus 231.4 ± 29.4mg in the fixed-dose group (p < 0.001).

Only one patient in the symptom-triggered group sustained a seizure. There were no seizures, hallucinations, or episodes of delirium tremens in any of the other 116 patients. The two treatment groups had similar quality-of-life and symptom scores aside from slightly higher physical functioning in the symptom-triggered group (p < 0.01). See Table 2.


Implication/Discussion:
Symptom-triggered administration of benzodiazepines in alcohol withdrawal led to a six-fold reduction in cumulative benzodiazepine use and a much shorter duration of pharmacotherapy than fixed-schedule administration. This more restrictive and responsive strategy did not increase the risk of major adverse outcomes such as seizure or DTs, and also did not result in increased patient discomfort.

Overall, this study confirmed the findings of the landmark study by Saitz et al. from eight years prior. Additionally, this trial was larger and did not exclude patients with a prior history of withdrawal seizures or severe withdrawal. The fact that both studies took place in inpatient specialty psychiatry units limits their generalizability to our inpatient general medicine populations.

Why the initial 1994 study did not gain clinical traction remains unclear. Both studies have been well-cited over the ensuing decades, and the paradigm has shifted firmly toward symptom-triggered benzodiazepine regimens using the CIWA scale. A 2010 Cochrane review cites the 1994 study only, while Wiki Journal Club and 2 Minute Medicine have entries on this 2002 study but not on the equally impressive 1994 study.

Further Reading/References:
1. “Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial.” JAMA. 1994.
2. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)
3. Wiki Journal Club
4. 2 Minute Medicine
5. “Benzodiazepines for alcohol withdrawal.” Cochrane Database Syst Rev. 2010.

Summary by Duncan F. Moore, MD