Week 38 – POISE

“Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery: a randomised controlled trial”

aka the PeriOperative Ischemic Evaluation (POISE) trial

Lancet. 2008 May 31;371(9627):1839-47. [free full text]

Non-cardiac surgery is commonly associated with major cardiovascular complications. It has been hypothesized that perioperative beta blockade would reduce such events by attenuating the effects of the intraoperative increases in catecholamine levels. Prior to the 2008 POISE trial, small- and moderate-sized trials had revealed inconsistent results, alternately demonstrating benefit and non-benefit with perioperative beta blockade. The POISE trial was a large RCT designed to assess the benefit of extended-release metoprolol succinate (vs. placebo) in reducing major cardiovascular events in patients of elevated cardiovascular risk.

Population: patients age 45+ undergoing non-cardiac surgery with estimated LOS 24+ hrs and elevated risk of cardiac disease à either 1) hx of CAD, 2) peripheral vascular disease, 3) hospitalization for CHF within past 3 years, 4) undergoing major vascular surgery, 5) or any three of the following seven risk criteria: undergoing intrathoracic or intraperitoneal surgery, hx CHF, hx TIA, hx DM, Cr > 2.0, age 70+, or undergoing urgent/emergent surgery.

Notable exclusion criteria: HR < 50, 2nd or 3rd degree heart block, asthma, already on beta blocker, prior intolerance of beta blocker, hx CABG within 5 years and no cardiac ischemia since

Intervention: metoprolol succinate (extended-release) 100mg PO starting 2-4 hrs before surgery, additional 100mg at 6-12 hrs postoperatively, followed by 200mg daily for 30 days.

Patients unable to take PO meds postoperatively were given metoprolol infusion.

Comparison: placebo PO / IV at same frequency as metoprolol arm

Outcome:
Primary – composite of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest at 30 days

Secondary (at 30 days)

  • cardiovascular death
  • non-fatal MI
  • non-fatal cardiac arrest
  • all-cause mortality
  • non-cardiovascular death
  • MI
  • cardiac revascularization
  • stroke
  • non-fatal stroke
  • CHF
  • new, clinically significant atrial fibrillation
  • clinically significant hypotension
  • clinically significant bradycardia

Pre-specified subgroup analyses of primary outcome:

Results:
9298 patients were randomized. However, fraudulent activity was detected at participating sites in Iran and Colombia, and thus 947 patients from these sites were excluded from the final analyses. Ultimately, 4174 were randomized to the metoprolol group, and 4177 were randomized to the placebo group. There were no significant differences in baseline characteristics, pre-operative cardiac medications, surgery type, or anesthesia type between the two groups (see Table 1).

Regarding the primary outcome, metoprolol patients were less likely than placebo patients to experience the primary composite endpoint of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest (HR 0.84, 95% CI 0.70-0.99, p = 0.0399). See Figure 2A for the relevant Kaplan-Meier curve. Note that the curves separate distinctly within the first several days.

Regarding selected secondary outcomes (see Table 3 for full list), metoprolol patients were more likely to die from any cause (HR 1.33, 95% CI 1.03-1.74, p = 0.0317). See Figure 2D for the Kaplan-Meier curve for all-cause mortality. Note that the curves start to separate around day 10. Cause of death was analyzed, and the only group difference in attributable cause was an increased number of deaths due to sepsis or infection in the metoprolol group (data not shown). Metoprolol patients were more likely to sustain a stroke (HR 2.17, 95% CI 1.26-3.74, p = 0.0053) or a non-fatal stroke (HR 1.94, 95% CI 1.01-3.69, p = 0.0450). Of all patients who sustained a non-fatal stroke, only 15-20% made a full recovery. Metoprolol patients were less likely to sustain new-onset atrial fibrillation (HR 0.76, 95% CI 0.58-0.99, p = 0.0435) and less likely to sustain a non-fatal MI (HR 0.70, 95% CI 0.57-0.86, p = 0.0008). There were no group differences in risk of cardiovascular death or non-fatal cardiac arrest. Metoprolol patients were more likely to sustain clinically significant hypotension (HR 1.55, 95% CI 1.38-1.74, P < 0.0001) and clinically significant bradycardia (HR 2.74, 95% CI 2.19-3.43, p < 0.0001).

Subgroup analysis did not reveal any significant interaction with the primary outcome by RCRI, sex, type of surgery, or anesthesia type.

Implication/Discussion:
In patients with cardiovascular risk factors undergoing non-cardiac surgery, the perioperative initiation of beta blockade decreased the composite risk of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest and increased the overall mortality risk and risk of stroke.

This study affirms its central hypothesis – that blunting the catecholamine surge of surgery is beneficial from a cardiac standpoint. (Most patients in this study had an RCRI of 1 or 2.) However, the attendant increase in all-cause mortality is dramatic. The increased mortality is thought to result from delayed recognition of sepsis due to masking of tachycardia. Beta blockade may also limit the physiologic hemodynamic response necessary to successfully fight a serious infection. In retrospective analyses mentioned in the discussion, the investigators state that they cannot fully explain the increased risk of stroke in the metoprolol group. However, hypotension attributable to beta blockade explains about half of the increased number of strokes.

Overall, the authors conclude that “patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.”

A major limitation of this study is the fact that 10% of enrolled patients were discarded in analysis due to fraudulent activity at selected investigation sites. In terms of generalizability, it is important to remember that POISE excluded patients who were already on beta blockers.

Currently, per expert opinion at UpToDate, it is not recommended to initiate beta blockers preoperatively in order improve perioperative outcomes. POISE is an important piece of evidence underpinning the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery, which includes the following recommendations regarding beta blockers:

  • Beta blocker therapy should not be started on the day of surgery (Class III – Harm, Level B)
  • Continue beta blockers in patients who are on beta blockers chronically (Class I, Level B)
  • In patients with intermediate- or high-risk preoperative tests, it may be reasonable to begin beta blockers
  • In patients with ≥ 3 RCRI risk factors, it may be reasonable to begin beta blockers before surgery
  • Initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit in those with a long-term indication but no other RCRI risk factors
  • It may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably > 1 day before surgery

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Management of cardiac risk for noncardiac surgery”
4. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.

Summary by Duncan F. Moore, MD

Week 37 – PARADIGM-HF

“Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure”

by the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) investigators

N Engl J Med. 2014 Sep 11;371(11):993-1004. [free full text]

Thanks to the CONSENSUS and SOLVD trials, angiotensin-converting enzyme (ACE) inhibitors have been a cornerstone of the treatment of heart failure with reduced ejection fraction (HFrEF) for years.

Neprilysin is a neutral endopeptidase that degrades several peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Inhibiting neprilysin increases levels of these substances and thus counteracts the neurohormonal overactivation of heart failure (which would otherwise lead to vasoconstriction, sodium retention, and maladaptive remodeling). Prior experimental data has demonstrated that, in terms of cardiovascular outcomes, neprilysin inhibition with an ARB is superior to ARB monotherapy. However, a clinical trial of concurrent neprilysin-inhibitor and ACE inhibitor therapy resulted in unacceptably high rates of serious angioedema. This study sought to show improved cardiac and mortality outcomes with neprilysin inhibition plus an ARB when compared to enalapril alone.

Population:
Inclusion Criteria: ≥18 y/o; NYHA class II, III, or IV; LVEF ≤ 35%; BNP ≥ 150 or NT-proBNP ≥600

Exclusion Criteria: Symptomatic hypotension, SBP < 100mmHg at screening or 95mmHg at randomization, eGFR < 30, or decrease in eGFR by 25% between screening and randomization, K+ > 5.2, or history of angioedema/side effects to ACE inhibition or ARBs

Intervention: sacubitril/valsartan 200mg BID

Comparison: enalapril 10mg BID

Trial design notes: Screened patients were initially given sacubitril/valsartan, followed by enalapril in single blinded run-in phases, in order to ensure similar tolerance of the drugs prior to randomization. Subsequently, patients who tolerated both drugs were randomized in a double-blind manner to treatment with one of the drugs. 

Outcome:
Primary – composite of death from cardiovascular causes or first hospitalization for heart failure

Secondary


Results:
4187 patients were randomized to the sacubitril/valsartan group, and 4212 were randomized to the enalapril group.

The primary endpoint (composite death due to cardiovascular causes or first hospitalization for HF) occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (p < 0.001; NNT = 21). Death due to cardiovascular causes occurred 558 times in the sacubitril/valsartan group and 693 times in the enalapril group (13.3% vs. 16.5%, p < 0.001; NNT = 31). Hospitalization for heart failure occurred (at least once) 537 times in the sacubitril/valsartan group and 658 times in the enalapril group (12.8% vs. 15.6%, p <0.001; NNT = 36).

Regarding secondary outcomes, the mean change in KCCQ score was a reduction of 2.99 points (i.e. a worsening of symptoms) in the sacubitril/valsartan group, versus a reduction of 4.63 points in the enalapril group (p = 0.001). There was no significant group difference in time to new-onset atrial fibrillation or time to diminished renal function.

Regarding safety outcomes, patients in the sacubitril/valsartan group were more likely to have symptomatic hypotension compared to patients in the enalapril group (14.0% vs. 9.2%; p <0.001; NNH = 21). However, patients in the enalapril group were more likely to have cough, serum creatinine ≥2.5, or potassium ≥6.0 compared to sacubitril/valsartan (p value varies, all significant). There was no group difference in rates of angioedema (p = 0.13).


Implication/Discussion:
In patients with HFrEF, inhibition of both angiotensin II and neprilysin with sacubitril/valsartan significantly reduced the risk of cardiovascular death or hospitalization for heart failure when compared to treatment with enalapril alone.

This study had several strengths. The treatment with sacubitril/valsartan was compared to treatment with a dose of enalapril that had previously been shown to reduce mortality when compared with placebo. Furthermore, the study used a run-in phase to ensure that patients could tolerate an enalapril dose that had previously been shown to reduce mortality. Finally, more patients in the enalapril group than in the sacubitril/valsartan group stopped the study drug due to adverse effects (12.3% vs. 10.7%, p=0.03).

This study ushered in a new era in heart failure management and added a new medication class – Angiotensin Receptor-Neprilysin Inhibitors or ARNIs – to the arsenal of available heart failure drugs. Entresto (sacubitril/valsartan), the ARNI posterchild, has been advertised widely over the past several years. However, clinical use so far has been lower than expected. Novartis, Entresto’s drug maker, is currently sponsoring PARAGON-HF, a trial of Entresto in patients with heart failure with preserved ejection fraction (HFpEF).

The 2017 ACC/AHA update to the guidelines for management of symptomatic HFrEF states that primary inhibition of the renin-angiotensin system with an ARNI in conjunction with evidence-based beta blockade and aldosterone antagonism is a Class I recommendation (Level B evidence). However, it does not favor this regimen over the Level-A-evidence regimens of an ARB or ACE inhibitor substituted for the ARNI. Yet the new guidelines also state that patients who have chronic symptomatic HFrEF of NYHA class II or III and tolerate an ACE inhibitor or ARB should substitute an ARNI for the ACE inhibitor or ARB in order to further reduce morbidity and mortality (Class I recommendation, level B evidence). See pages 15 and 17 here to read the details.

Bottom line: Among patients with symptomatic HFrEF, treatment with an ARNI reduces cardiovascular mortality and HF hospitalizations when compared to treatment with enalapril. Due to this study’s impact, the use of ARNIs is now a Class I recommendation by the 2017 ACC/AHA guidelines for the treatment of HFrEF. Despite its higher cost, the use of sacubitril/valsartan appears to be cost-effective in terms of QALYs gained.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. ACC/AHA 2017 Focused Update for Guideline Management of Heart Failure
4. CardioBrief, “After Slow Start Entresto Is Poised For Takeoff.”
5. PARAGON-HF @ ClinicalTrials.gov
6. McMurray et al., “Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction.” Heart, 2017.

Summary by Patrick Miller, MD

Week 36 – Rivers Trial

“Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock”

N Engl J Med. 2001 Nov 8;345(19):1368-77. [free full text]

Sepsis is common, and severe sepsis and septic shock confer high mortality risks. Fundamentally, sepsis is a global mismatch between oxygen demand and delivery. Around the time of this seminal study by Rivers et al., there was increasing recognition of the concept of the “golden hour” in sepsis management – “where definitive recognition and treatment provide maximal benefit in terms of outcome” (1368). Rivers and his team created a “bundle” of early sepsis interventions that targeted preload, afterload, and contractility, dubbed early goal-directed therapy (EGDT), and evaluated this bundle’s effect on mortality and end-organ dysfunction.

Population: adults presenting to a single US academic center ED with ≥ 2 SIRS criteria and SBP ≤ 90 after a crystalloid challenge of 20-30ml/kg over 30min or lactate > 4mmol/L.

Notable exclusion criteria: acute CVA, MI, ACS, pulmonary edema, cardiac dysrhythmias, contraindication to central line, active GIB, trauma, “uncured cancer,” immunosuppression, or DNR status

Intervention: early goal-directed therapy

  • received a central venous catheter with continuous central venous O2 saturation (ScvO2) measurement
  • treated according to EGDT protocol (see Figure 2, or below) in ED for at least six hours
    • 500ml bolus of crystalloid q30min to achieve CVP 8-12mm
    • vasopressors to achieve MAP ≥ 65
    • vasodilators to achieve MAP ≤ 90
    • if ScvO2 < 70%, transfuse RBCs to achieve Hct ≥ 30
    • if, after CVP, MAP, and Hct were thusly optimized and ScvO2 remained < 70%, dobutamine was added and uptitrated to achieve ScvO2 ≥ 70 or until max dose 20 μg/kg/min
      • dobutamine was de-escalated if MAP < 65 or HR > 120
    • patients in whom hemodynamics could not be optimized were intubated and sedated, in order to decrease oxygen consumption
  • then transferred to inpatient ICU bed as soon as able, at which time ScvO2 measurement was discontinued
  • inpatient team was blinded to treatment group assignment

Comparison: standard of care

Outcome:
Primary – in-hospital mortality

Secondary

  • resuscitation end points
  • organ-dysfunction scores
  • coagulation-related variables
  • administered treatments
  • consumption of healthcare resources


Results
:
130 patients were randomized to EGDT, and 133 to standard therapy. There were no differences in baseline characteristics (see Table 1). There was no group difference in the prevalence of antibiotics given within the first 6 hours. Standard-therapy patients spent 6.3 ± 3.2 hours in the ED, whereas EGDT patients spent 8.0 ± 2.1 (p < 0.001).

In-hospital mortality was 46.5% in the standard-therapy group, and 30.5% in the EGDT group (p = 0.009, NNT 6.25); 28-day and 60-day mortalities were also improved in the EGDT group. See Table 3.

During the initial six hours of resuscitation, there was no significant group difference in mean heart rate or CVP. MAP was higher in the EGDT group (p < 0.001), but all patients in both groups reached a MAP ≥ 65. ScvO2 ≥ 70% was met by 60.2% of standard-therapy patients and 94.9% of EGDT patients (p < 0.001). A combination endpoint of achievement of CVP, MAP, and UOP (≥ 0.5cc/kg/hr) goals was met by 86.1% of standard-therapy patients and 99.2% of EGDT patients (p < 0.001). Standard-therapy patients had lower ScvO2 and greater base deficit, while lactate and pH values were similar in both groups.

During the period of 7 to 72 hours, the organ-dysfunction scores of APACHE II, SAPS II, and MODS were higher in the standard-therapy group (see Table 2). The prothrombin time, fibrin-split products concentration, and d-dimer concentrations were higher in the standard-therapy group, while PTT, fibrinogen concentration, and platelet counts were similar.

During the initial six hours, EGDT patients received significantly more fluids, pRBCs, and inotropic support than standard-therapy patients. Rates of vasopressor use and mechanical ventilation were similar.

During the period of 7 to 72 hours, standard-therapy patients received more fluids, pRBCs, and vasopressors than the EGDT group, and were more likely to be intubated and to have pulmonary-artery catheterization. Rates of inotrope use were similar.

Overall, during the first 72 hrs, standard-therapy patients were more likely to receive vasopressors, be intubated, and undergo pulmonary-artery catheterization. EGDT patients were more likely to receive pRBC transfusion. There was no group difference in total volume of fluid administration or inotrope use.

Regarding utilization, there were no group differences in mean duration of vasopressor therapy, mechanical ventilation, or length of stay. Among patients who survived to discharge, standard-therapy patients spent longer in the hospital than EGDT patients (18.4 ± 15.0 vs. 14.6 ± 14.5 days, respectively, p = 0.04).

Implication/Discussion:
Early goal-directed therapy reduced in-hospital mortality in patients presenting to the ED with severe sepsis or septic shock, when compared with usual care.

In their discussion, the authors note that “when early therapy is not comprehensive, the progression to severe disease may be well under way at the time of admission to the intensive care unit” (1376).

The Rivers trial has been cited over 10,100 times. It has been widely discussed and dissected for decades. Most importantly, it helped catalyze a then-ongoing paradigm shift of what “usual care” in sepsis is.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “Though we do not use the ‘Rivers protocol’ as written, concepts (timely resuscitation) have certainly infiltrated our ‘standard of care’ approach.”

The Rivers trial evaluated the effect of a bundle (multiple interventions). It was a relatively complex protocol, and the transfusion of blood to Hgb > 10 may have caused significant harm.

In aggregate, the most critical elements of the modern initial resuscitation in sepsis are early administration of antibiotics (notably not protocolized by Rivers) within the first hour and the aggressive administration of IV fluids (now usually 30cc/kg of crystalloid within the first 3 hours of presentation).

More recently, there have been three large RCTs of EGDT versus usual care and/or protocols that used some of the EGDT targets: ProCESS (2014, USA), ARISE (2014, Australia), and ProMISe (2015, UK). In general terms, EGDT provided no mortality benefit compared to usual care. Prospectively, the authors of these three trials planned a meta-analysis – the 2017 PRISM study – which concluded that “EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics.” Despite patients in the Rivers trial being sicker than those of ProCESS/ARISE/ProMISe, it was not found in the subgroup analysis of PRISM that EGDT was more beneficial in sicker patients. Overall, the PRISM authors noted that “it remains possible that general advances in the provision of care for sepsis and septic shock, to the benefit of all patients, explain part or all of the difference in findings between the trial by Rivers et al. and the more recent trials.”

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Life in The Fast Lane
4. “A randomized trial of protocol-based care for early septic shock” (ProCESS). NEJM 2014.
5. “Goal-directed resuscitation for patients with early septic shock” (ARISE). NEJM 2014.
6. “Trial of early, goal-directed resuscitation for septic shock” (ProMISe). NEJM 2015.
7. “Early, Goal-Directed Therapy for Septic Shock – A Patient-level Meta-Analysis” PRISM. NEJM 2017.
8. Surviving Sepsis Campaign
9. UpToDate, “Evaluation and management of suspected sepsis and septic shock in adults

Summary by Duncan F. Moore, MD

Week 35 – PLCO

“Mortality Results from a Randomized Prostate-Cancer Screening Trial”

by the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial project team

N Engl J Med. 2009 Mar 26;360(13):1310-9. [free full text]

The use of prostate-specific-antigen (PSA) testing to screen for prostate cancer has been a contentious subject for decades. Prior to the 2009 PLCO trial, there were no high-quality prospective studies of the potential benefit of PSA testing.

Population: men ages 55-74 enrolled at 10 US academic centers

exclusion criteria – hx of prostate, lung, or colorectal cancer, current cancer tx, and > 1 PSA test in past 3 years

Intervention: annual PSA testing for 6 years with annual digital rectal exam (DRE) for 4 years

Comparison: usual care

Outcome:
Primary – prostate-cancer-attributable death rate
Secondary – incidence of prostate cancer

Subgroup analyses of primary outcome:

  • patients with no more than 1 PSA test prior to enrollment
  • patients with 2+ PSA tests prior to enrollment

Results:
38,343 patients were randomized to the screening group, and 38,350 were randomized to the usual-care group. Baseline characteristics were similar in both groups. Median follow-up duration was 11.5 years. Patients in the screening group were 85% compliant with PSA testing and 86% compliant with DRE. In the usual-care group, 40% of patients received a PSA test within the first year, and 52% received a PSA test by the sixth year. Cumulative DRE rates in the control group were between 40-50%.

By seven years, there was no significant difference in rates of death attributable to prostate cancer. There were 50 deaths in the screening group and only 44 in the usual-care group (rate ratio 1.13, 95% CI 0.75 – 1.70). At ten years, there were 92 and 82 deaths in the respective groups (rate ratio 1.11, 95% CI 0.83–1.50).

By seven years, there was a higher rate of prostate cancer detection in the screening group. 2820 patients were diagnosed in the screening group, but only 2322 were diagnosed in the usual-care group (rate ratio 1.22, 95% CI 1.16–1.29). By ten years, there were 3452 and 2974 diagnoses in the respective groups (rate ratio 1.17, 95% CI 1.11–1.22).

Treatment-related complications (e.g. infection, incontinence, impotence) were not reported in this study.

Implication/Discussion:
Yearly PSA screening increased the prostate cancer diagnosis rate but did not impact prostate-cancer mortality when compared to the standard of care.

However, there were relatively high rates of PSA testing in the usual-care group (40-50%). The authors cite this finding as a probable major contributor to the lack of mortality difference. Other factors that may have biased to a null result were prior PSA testing and advances in treatments for prostate cancer during the trial. Regarding the former, 44% of men in both groups had already had one or more PSA tests prior to study enrollment. Prior PSA testing likely contributed to selection bias.

PSA screening recommendations prior to this 2009 study:

  • American Urological Association and American Cancer Society – recommended annual PSA and DRE, starting at age 50 if normal risk and earlier in high-risk men
  • National Comprehensive Cancer Network: “a risk-based screening algorithm, including family history, race, and age”
  • 2008 USPSTF Guidelines: insufficient evidence to determine balance between risks/benefits of PSA testing in men younger than 75; recommended against screening in age 75+ (Grade I Recommendation)

The authors of this study conclude that their results “support the validity of the recent [2008] recommendations of the USPSTF, especially against screening all men over the age of 75.”

However, the conclusions of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which was published concurrently with PLCO in NEJM, differed. In ERSPC, PSA was screened every 4 years. The authors found an increased rate of detection of prostate cancer, but, more importantly, they found that screening decreased prostate cancer mortality (adjusted rate ratio 0.80, 95% CI 0.65–0.98, p = 0.04; NNT 1410 men receiving 1.7 screening visits over 9 years). Like PLCO, this study did not report treatment harms that may have been associated with overly zealous diagnosis.

The USPSTF reexamined its PSA guidelines in 2012. Given the lack of mortality benefit in PLCO, the pitiful mortality benefit in ERSPC, and the assumed harm from over-diagnosis and excessive intervention in patients who would ultimately not succumb to prostate cancer, the USPSTF concluded that PSA-based screening for prostate cancer should not be offered (Grade D Recommendation).

However, this guideline is under active consideration as of March 2018. See https://screeningforprostatecancer.org/. The draft recommendations encourage men ages 55-69 to have an informed discussion with their physician about potential benefits and harms of PSA-based screening (Grade C Recommendation). The USPSTF continues to recommend against screening in patients over 70 years old.

Screening for prostate cancer remains a complex and controversial topic. While we await further guidelines, we should continue to provide our patients with the aforementioned informed discussion. UpToDate has a nice summary of talking points culled from several sources.

Further Reading/References:
1. 2 Minute Medicine
2. ERSPC @ Wiki Journal Club
3. UpToDate, Screening for Prostate Cancer

Summary by Duncan F. Moore, MD

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]

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]

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]

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]

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

Week 30 – Omeprazole for Bleeding Peptic Ulcers

“Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Treatment of Bleeding Peptic Ulcers”

N Engl J Med. 2000 Aug 3;343(5):310-6. [free full text]

Intravenous proton-pump inhibitor (PPI) therapy is a cornerstone of modern therapy for bleeding peptic ulcers. However, prior to this 2000 study by Lau et al., the role of PPIs in the prevention of recurrent bleeding after endoscopic treatment was unclear. At the time, re-bleeding rates after endoscopic treatment were noted to be approximately 15-20%. Although other studies had approached this question, no high-quality, large, blinded RCT had examined adjuvant PPI use immediately following endoscopic treatment.

Population: patients with bleeding gastroduodenal ulcer visualized on endoscopy in whom hemostasis was achieved following epinephrine injection and thermocoagulation (consecutive patients, single center in Hong Kong)

Intervention: omeprazole 80mg IV bolus followed by 8mg/hr infusion x72 hrs, followed by omeprazole 20mg PO x8 wks

Comparison: placebo bolus + drip x72 hrs, followed by omeprazole 20mg PO x8 wks

Outcome:
Primary – Recurrent bleeding within 30 days

Secondary

  1. Recurrent bleeding within 72 hrs
  2. Mean number of units of blood transfused within 30 days
  3. Duration of hospitalization
  4. All-cause mortality at 30 days


Results
:
120 patients were randomized to each arm. The two groups had similar baseline characteristics, including ulcer-specific characteristics. The trial was terminated early due to the finding on interim analysis of a significantly lower recurrent bleeding rate in the omeprazole arm.

Bleeding re-occurred within 30 days in 8 (6.7%) omeprazole patients versus 27 (22.5%) placebo patients (HR 3.9, 95% CI 1.7-9.0; NNT 6.3). A Cox proportional-hazards model, when adjusted for size and location of ulcers, presence/absence of coexisting illness, and history of ulcer disease, revealed a similar hazard ratio (HR 3.9, 95% CI 1.7-9.1).

Recurrent bleeding was most common during the first 72 hrs (4.2% of the omeprazole group versus 20% of the placebo group, RR 4.80, 95% CI 1.89-12.2, p<0.001). For a nice visualization of the early separation of re-bleeding rates, see the Kaplan-Meier curve in Figure 1.

The mean number of units of blood transfused within 30 days was 2.7 ± 2.5 in the omeprazole group versus 3.5 ± 3.8 in the placebo group (p = 0.04). The number of units transfused after the initial endoscopic treatment was 1.7 ± 1.9 in the omeprazole group versus 2.4 ± 3.2 in the placebo group (p = 0.03).

Regarding duration of hospitalization, 46.7% of omeprazole patients were admitted for < 5 days versus 31.7% of placebo patients (p = 0.02). Median stay was 4 days in the omeprazole group versus 5 days in the placebo group (p = 0.006).

4.2% of the omeprazole patients died within 30 days, whereas 10% of the placebo patients died (p = 0.13).

Implication/Discussion:
Treatment with intravenous omeprazole immediately following endoscopic intervention for bleeding peptic ulcer significantly reduced the rate of recurrent bleeding. This effect was most prominent within the first 3 days of therapy. This intervention also reduced blood transfusion requirements and shortened hospital stays.

The presumed mechanism of action is increased gastric pH facilitating platelet aggregation.

In 2018, the benefit of this intervention seems so obvious based on its description alone, that one would imagine that such a trial would not be funded or published in such a high-profile journal. However, the annals of medicine are littered with now-discarded interventions that made sense from a theoretical or mechanistic perspective but were demonstrated to be ineffective or even harmful (e.g. pharmacologic suppression of ventricular arrhythmias post-MI or renal denervation for refractory HTN).

Today, bleeding peptic ulcers are treated with an IV PPI twice daily. Per UpToDate, meta-analyses have not shown a benefit of continuous PPI infusion over this IV BID dosing. However, per 2012 guidelines in the American Journal of Gastroenterology, patients with active bleeding or non-bleeding visible vessels should receive both endoscopic intervention and IV PPI bolus followed by infusion.


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Overview of the Treatment of Bleeding Peptic Ulcers”
4. Laine L, Jensen DM. “Management of patients with ulcer bleeding.” Am J Gastroenterol. 2012.

Summary by Duncan F. Moore, MD

Week 29 – ALLHAT

“Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs. Diuretic”

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

JAMA. 2002 Dec 18;288(23):2981-97. [free full text]

Hypertension is a ubiquitous disease, and the cardiovascular and mortality benefits of BP control have been well described. However, as the number of available antihypertensive classes proliferated in the past several decades, a head-to-head comparison of different antihypertensive regimens was necessary to determine the optimal first-step therapy. The 2002 ALLHAT trial was a landmark trial in this effort.

Population:
33,357 patients aged 55 years or older with hypertension and at least one other coronary heart disease (CHD) risk factor (previous MI or stroke, LVH by ECG or echo, T2DM, current cigarette smoking, HDL < 35 mg/dL, or documentation of other atherosclerotic cardiovascular disease (CVD)). Notable exclusion criteria: history of hospitalization for CHF, history of treated symptomatic CHF, or known LVEF < 35%.

Intervention:
Prior antihypertensives were discontinued upon initiation of the study drug. Patients were randomized to one of three study drugs in a double-blind fashion. Study drugs and additional drugs were added in a step-wise fashion to achieve a goal BP <140/90 mmHg.

Step 1: titrate assigned study drug

  • chlorthalidone: 12.5 –> (sham titration) –> 25 mg/day
  • amlodipine: 2.5 –> 5 –> 10 mg/day
  • lisinopril: 10 –> 20 –> 40 mg/day

Step 2: add open-label agents at treating physician’s discretion (atenolol, clonidine, or reserpine)

  • atenolol: 25 to 100 mg/day
  • reserpine: 0.05 to 0.2 mg/day
  • clonidine: 0.1 to 0.3 mg BID

Step 3: add hydralazine 25 to 100 mg BID

Comparison:
Pairwise comparisons with respect to outcomes of chlorthalidone vs. either amlodipine or lisinopril. A doxazosin arm existed initially, but it was terminated early due to an excess of CV events, primarily driven by CHF.


Outcomes
:

Primary –  combined fatal CAD or nonfatal MI

Secondary

  • all-cause mortality
  • fatal and nonfatal stroke
  • combined CHD (primary outcome, PCI, or hospitalized angina)
  • combined CVD (CHD, stroke, non-hospitalized treated angina, CHF [fatal, hospitalized, or treated non-hospitalized], and PAD)

Results:
Over a mean follow-up period of 4.9 years, there was no difference between the groups in either the primary outcome or all-cause mortality.

When compared with chlorthalidone at 5 years, the amlodipine and lisinopril groups had significantly higher systolic blood pressures (by 0.8 mmHg and 2 mmHg, respectively). The amlodipine group had a lower diastolic blood pressure when compared to the chlorthalidone group (0.8 mmHg).

When comparing amlodipine to chlorthalidone for the pre-specified secondary outcomes, amlodipine was associated with an increased risk of heart failure (RR 1.38; 95% CI 1.25-1.52).

When comparing lisinopril to chlorthalidone for the pre-specified secondary outcomes, lisinopril was associated with an increased risk of stroke (RR 1.15; 95% CI 1.02-1.30), combined CVD (RR 1.10; 95% CI 1.05-1.16), and heart failure (RR 1.20; 95% CI 1.09-1.34). The increased risk of stroke was mostly driven by 3 subgroups: women (RR 1.22; 95% CI 1.01-1.46), blacks (RR 1.40; 95% CI 1.17-1.68), and non-diabetics (RR 1.23; 95% CI 1.05-1.44). The increased risk of CVD was statistically significant in all subgroups except in patients aged less than 65. The increased risk of heart failure was statistically significant in all subgroups.


Discussion
:
In patients with hypertension and one risk factor for CAD, chlorthalidone, lisinopril, and amlodipine performed similarly in reducing the risks of fatal CAD and nonfatal MI.

The study has several strengths: a large and diverse study population, a randomized, double-blind structure, and the rigorous evaluation of three of the most commonly prescribed “newer” classes of antihypertensives. Unfortunately, neither an ARB nor an aldosterone antagonist was included in the study. Additionally, the step-up therapies were not reflective of contemporary practice. (Instead, patients would likely be prescribed one or more of the primary study drugs.)

The ALLHAT study is one of the hallmark studies of hypertension and has played an important role in hypertension guidelines since it was published. Following the publication of ALLHAT, thiazide diuretics became widely used as first line drugs in the treatment of hypertension. The low cost of thiazides and their limited side-effect profile are particularly attractive class features. While ALLHAT looked specifically at chlorthalidone, in practice the positive findings were attributed to HCTZ, which has been more often prescribed. The authors of ALLHAT argued that the superiority of thiazides was likely a class effect, but according to the analysis at Wiki Journal Club, “there is little direct evidence that HCTZ specifically reduces the incidence of CVD among hypertensive individuals.” Furthermore, a 2006 study noted that that HCTZ has worse 24-hour BP control than chlorthalidone due to a shorter half-life. The ALLHAT authors note that “since a large proportion of participants required more than 1 drug to control their BP, it is reasonable to infer that a diuretic be included in all multi-drug regimens, if possible.” The 2017 ACC/AHA High Blood Pressure Guidelines state that, of the four thiazide diuretics on the market, chlorthalidone is preferred because of a prolonged half-life and trial-proven reduction of CVD (via the ALLHAT study).

Further Reading / References:
1. 2017 ACC Hypertension Guidelines
2. Wiki Journal Club
3. 2 Minute Medicine
4. Ernst et al, “Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.” (2006)
5. Gillis Pharmaceuticals: https://www.youtube.com/watch?v=HOxuAtehumc
6. Concepts in Hypertension, Volume 2 Issue 6

Summary by Ryan Commins, MD