“Apixaban versus Warfarin in Patients with Atrial Fibrillation”

N Engl J Med. 2011 Sep 15;365(11):981-92. [free full text]

Prior to the development of the DOACs, warfarin was the standard of care for the reduction of risk of stroke in atrial fibrillation. Drawbacks of warfarin include a narrow therapeutic range, numerous drug and dietary interactions, the need for frequent monitoring, and elevated bleeding risk. Around 2010, the definitive RCTs for the oral direct thrombin inhibitor dabigatran (RE-LY) and the oral factor Xa inhibitor rivaroxaban (ROCKET AF) showed equivalence or superiority to warfarin. Shortly afterward, the ARISTOTLE trial demonstrated the superiority of the oral factor Xa inhibitor apixaban (Eliquis).

The trial enrolled patients with atrial fibrillation or flutter with at least one additional risk factor for stroke (age 75+, prior CVA/TIA, symptomatic CHF, or reduced LVEF). Notably, patients with Cr > 2.5 were excluded. Patients were randomized to treatment with either apixaban BID + placebo warfarin daily (reduced 2.5mg apixaban dose given in patients with 2 or more of the following: age 80+, weight < 60, Cr > 1.5) or to placebo apixaban BID + warfarin daily. The primary efficacy outcome was the incidence of stroke, and the primary safety outcome was “major bleeding” (clinically overt and accompanied by Hgb drop of ≥ 2, “occurring at a critical site,” or resulting in death). Secondary outcomes included all-cause mortality and a composite of major bleeding and “clinically-relevant non-major bleeding.”

9120 patients were assigned to the apixaban group, and 9081 were assigned to the warfarin group. Mean CHADS2 score was 2.1. Fewer patients in the apixaban group discontinued their assigned study drug. Median duration of follow-up was 1.8 years. The incidence of stroke was 1.27% per year in the apixaban group vs. 1.60% per year in the warfarin group (HR 0.79, 95% CI 0.66-0.95, p<0.001). This reduction was consistent across all major subgroups (see Figure 2). Notably, the rate of hemorrhagic stroke was 49% lower in the apixaban group, and the rate of ischemic stroke was 8% lower in the apixaban group. All-cause mortality was 3.52% per year in the apixaban group vs. 3.94% per year in the warfarin group (HR 0.89, 95% CI 0.80-0.999, p=0.047). The incidence of major bleeding was 2.13% per year in the apixaban group vs. 3.09% per year in the warfarin group (HR 0.69, 95% CI 0.60-0.80, p<0.001). The rate of intracranial hemorrhage was 0.33% per year in the apixaban group vs. 0.80% per year in the warfarin group (HR 0.42, 95% CI 0.30-0.58, p<0.001). The rate of any bleeding was 18.1% per year in the apixaban group vs. 25.8% in the warfarin group (p<0.001).

In patients with non-valvular atrial fibrillation and at least one other risk factor for stroke, anticoagulation with apixaban significantly reduced the risk of stroke, major bleeding, and all-cause mortality relative to anticoagulation with warfarin. This was a large RCT that was designed and powered to demonstrate non-inferiority but in fact was able to demonstrate the superiority of apixaban. Along with ROCKET AF and RE-LY, the ARISTOTLE trial ushered in the modern era of DOACs in atrial fibrillation. Apixaban was approved by the FDA for the treatment of non-valvular atrial fibrillation in 2012. Patient prescription cost is no longer a major barrier to prescription. These three major DOACs are all preferred in the DC Medicaid formulary (see page 14). To date, no trial has compared the various DOACs directly.

Further Reading/References:
1. ARISTOTLE @ Wiki Journal Club
2. 2 Minute Medicine
3. “Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost-effectiveness analysis,” BMJ 2017

Summary by Duncan F. Moore, MD

Week 25 – 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.

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%.

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 –> 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

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.

Primary –  combined fatal CAD or nonfatal MI


  • 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)

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.

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

Image Credit: Kimivanil, CC BY-SA 4.0, via Wikimedia Commons

Week 22 – RALES

“The effect of spironolactone on morbidity and mortality in patients with severe heart failure”

by the Randomized Aldactone Evaluation Study Investigators

N Engl J Med. 1999 Sep 2;341(10):709-17. [free full text]

Inhibition of the renin-angiotensin-aldosterone system (RAAS) is a tenet of the treatment of heart failure with reduced ejection fraction (see post from Week 6 – SOLVD). However, physiologic evidence exists that suggests ACEis only partially inhibit aldosterone production. It had been hypothesized that aldosterone receptor blockade (e.g. with spironolactone) in conjunction with ACE inhibition could synergistically improve RAAS blockade; however, there was substantial clinician concern about the risk of hyperkalemia. In 1996, the RALES investigators demonstrated that the addition of spironolactone 12.5 or 25mg daily in combination with ACEi resulted in laboratory evidence of increased RAAS inhibition at 12 weeks with an acceptable increased risk of hyperkalemia. The 1999 RALES study was thus designed to evaluate prospectively the mortality benefit and safety of the addition of relatively low-dose aldosterone treatment to the standard HFrEF treatment regimen.

The study enrolled patients with severe HFrEF (LVEF ≤ 35% and NYHA class IV symptoms within the past 6 months and class III or IV symptoms at enrollment) currently being treated with an ACEi (if tolerated) and a loop diuretic. Patients were randomized to the addition of spironolactone 25mg PO daily or placebo. (The dose could be increased at 8 weeks to 50mg PO daily if the patient showed signs or symptoms of progression of CHF without evidence of hyperkalemia.) The primary outcome was all-cause mortality. Secondary outcomes included death from cardiac causes, hospitalization for cardiac causes, change in NYHA functional class, and incidence of hyperkalemia.

1663 patients were randomized. The trial was stopped early (mean follow-up of 24 months) due to the marked improvement in mortality among the spironolactone group. Among the placebo group, 386 (46%) patients died, whereas only 284 (35%) patients among the spironolactone group died (RR 0.70, 95% CI 0.60 to 0.82, p < 0.001; NNT = 8.8). See the dramatic Kaplan-Meier curve in Figure 1. Relative to placebo, spironolactone treatment reduced deaths secondary to cardiac causes by 31% and hospitalizations for cardiac causes by 30% (p < 0.001 for both). In placebo patients, NYHA class improved in 33% of cases, was unchanged in 18%, and worsened in 48% of patients; in spironolactone patients, the NYHA class improved in 41%, was unchanged in 21%, and worsened in 38% of patients (p < 0.001 for group difference by Wilcoxon test). “Serious hyperkalemia” occurred in 10 (1%) of placebo patients and 14 (2%) of spironolactone patients (p = 0.42). Treatment discontinuation rates were similar among the two groups.

Among patients with severe HFrEF, the addition of spironolactone improved mortality, reduced hospitalizations for cardiac causes, and improved symptoms without conferring an increased risk of serious hyperkalemia. The authors hypothesized that spironolactone “can prevent progressive heart failure by averting sodium retention and myocardial fibrosis” and can “prevent sudden death from cardiac causes by averting potassium loss and by increasing the myocardial uptake of norepinephrine.” Myocardial fibrosis is thought to be reduced via blocking the role aldosterone plays in collagen formation. Overall, this was a well-designed double-blind RCT that built upon the safety data of the safe-dose-finding 1996 RALES trial and ushered in the era of routine use of aldosterone receptor blockade in severe HFrEF. In 2003, the EPHESUS trial trial demonstrated a mortality benefit of aldosterone antagonism (with eplerenone) among patients with LV dysfunction following acute MI, and in 2011, the EMPHASIS-HF trial demonstrated a reduction in CV death or HF hospitalization with eplerenone use among patients with EF ≤ 35% and NYHA class II symptoms (and notably among patients with a much higher prevalence of beta-blocker use than those of the mid-1990s RALES cohort). The 2014 TOPCAT trial demonstrated that, among patients with HFpEF, spironolactone does not reduce a composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations.

The 2013 ACCF/AHA Guideline for the Management of Heart Failure recommends the use of aldosterone receptor antagonists in patients with NYHA class II-IV symptoms with LVEF ≤ 35% and following an acute MI in patients with LVEF ≤ 40% with symptomatic HF or with a history of diabetes mellitus. Contraindications include Cr ≥ 2.5 or K ≥ 5.0.

Further Reading/References:
1. “Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]).” American Journal of Cardiology, 1996.
2. RALES @ Wiki Journal Club
3. RALES @ 2 Minute Medicine
4. EPHESUS @ Wiki Journal Club
5. EMPHASIS-HF @ Wiki Journal Club
6. TOPCAT @ Wiki Journal Club
7. 2013 ACCF/AHA Guideline for the Management of Heart Failure

Summary by Duncan F. Moore, MD

Image Credit: Spirono, CC0 1.0, via Wikimedia Commons


“Effect of carvedilol on survival in severe chronic heart failure”

by the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group

N Engl J Med. 2001 May 31;344(22):1651-8. [free full text]

We are all familiar with the role of beta-blockers in the management of heart failure with reduced ejection fraction. In the late 1990s, a growing body of excellent RCTs demonstrated that metoprolol succinate, bisoprolol, and carvedilol improved morbidity and mortality in patients with mild to moderate HFrEF. However, the only trial of beta-blockade (with bucindolol) in patients with severe HFrEF failed to demonstrate a mortality benefit. In 2001, the COPERNICUS trial further elucidated the mortality benefit of carvedilol in patients with severe HFrEF.

The study enrolled patients with severe CHF (NYHA class III-IV symptoms and LVEF < 25%) despite “appropriate conventional therapy” and randomized them to treatment with carvedilol with protocolized uptitration (in addition to pt’s usual meds) or placebo with protocolized uptitration (in addition to pt’s usual meds). The major outcomes measured were all-cause mortality and the combined risk of death or hospitalization for any cause.

2289 patients were randomized before the trial was stopped early due to higher than expected survival benefit in the carvedilol arm. Mean follow-up was 10.4 months. Regarding mortality, 190 (16.8%) of placebo patients died, while only 130 (11.2%) of carvedilol patients died (p = 0.0014) (NNT = 17.9). Regarding mortality or hospitalization, 507 (44.7%) of placebo patients died or were hospitalized, but only 425 (36.8%) of carvedilol patients died or were hospitalized (NNT = 12.6). Both outcomes were found to be of similar directions and magnitudes in subgroup analyses (age, sex, LVEF < 20% or >20%, ischemic vs. non-ischemic CHF, study site location, and no CHF hospitalization within year preceding randomization).

In severe HFrEF, carvedilol significantly reduces mortality and hospitalization risk.

This was a straightforward, well-designed, double-blind RCT with a compelling conclusion. In addition, the dropout rate was higher in the placebo arm than the carvedilol arm! Despite longstanding clinician fears that beta-blockade would be ineffective or even harmful in patients with already advanced (but compensated) HFrEF, this trial definitively established the role for beta-blockade in such patients.

Per the 2013 ACCF/AHA guidelines, “use of one of the three beta blockers proven to reduce mortality (e.g. bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF, unless contraindicated.”

Please note that there are two COPERNICUS trials. This is the first reported study (NEJM 2001) which reports only the mortality and mortality + hospitalization results, again in the context of a highly anticipated trial that was terminated early due to mortality benefit. A year later, the full results were published in Circulation, which described findings such as a decreased number of hospitalizations, fewer total hospitalization days, fewer days hospitalized for CHF, improved subjective scores, and fewer serious adverse events (e.g. sudden death, cardiogenic shock, VT) in the carvedilol arm.

Further Reading/References:
1. 2013 ACCF/AHA Guideline for the Management of Heart Failure
2. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
3. COPERNICUS, 2002 Circulation version
4. Wiki Journal Club (describes 2001 NEJM, cites 2002 Circulation)
5. 2 Minute Medicine (describes and cites 2002 Circulation)

Summary by Duncan F. Moore, MD

Week 17 – 4S

“Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)”

Lancet. 1994 Nov 19;344(8934):1383-9 [free full text]

Statins are an integral part of modern primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Hypercholesterolemia is regarded as a major contributory factor to the development of atherosclerosis, and in the 1980s, a handful of clinical trials demonstrated reduction in MI/CAD incidence with cholesterol-lowering agents, such as cholestyramine and gemfibrozil. However, neither drug demonstrated a mortality benefit. By the late 1980s, there was much hope that the emerging drug class of HMG-CoA reductase inhibitors (statins) would confer a mortality benefit, given their previously demonstrated LDL-lowering effects. The 1994 Scandinavian Simvastatin Survival Study was the first large clinical trial to assess this hypothesis.

4444 adults ages 35-70 with a history of angina pectoris or MI and elevated serum total cholesterol (212 – 309 mg/dL) were recruited from 94 clinical centers in Scandinavia (and in Finland, which is technically a Nordic country but not a Scandinavian country…) and randomized to treatment with either simvastatin 20mg PO qPM or placebo. Dosage was increased at 12 weeks and 6 months to target a serum total cholesterol of 124 to 201 mg/dL. (Placebo patients were randomly uptitrated as well.) The primary endpoint was all-cause mortality. The secondary endpoint was time to first “major coronary event,” which included coronary deaths, nonfatal MI, resuscitated cardiac arrest, and definite silent MI per EKG.

The study was stopped early in 1994 after an interim analysis demonstrated a significant survival benefit in the treatment arm. At a mean 5.4 years of follow-up, 256 (12%) in the placebo group versus 182 (8%) in the simvastatin group had died (RR 0.70, 95% CI 0.58-0.85, p=0.0003, NNT = 30.1). The mortality benefit was driven exclusively by a reduction in coronary deaths. Dropout rates were similar (13% of placebo group and 10% of simvastatin group). The secondary endpoint, occurrence of a major coronary event, occurred in 622 (28%) of the placebo group and 431 (19%) of the simvastatin group (RR 0.66, 95% CI 0.59-0.75, p < 0.00001). Subgroup analyses of women and patients aged 60+ demonstrated similar findings for the primary and secondary outcomes. Over the entire course of the study, the average changes in lipid values from baseline in the simvastatin group were -25% total cholesterol, -35% LDL, +8% HDL, and -10% triglycerides. The corresponding percent changes from baseline in the placebo group were +1%, +1%, +1%, and +7%, respectively.

In conclusion, simvastatin therapy reduced mortality in patients with known CAD and hypercholesterolemia via reduction of major coronary events. This was a large, well-designed, double-blind RCT that ushered in the era of widespread statin use for secondary, and eventually, primary prevention of ASCVD. For further information about modern guidelines for the use of statins, please see the 2013 “ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” and the 2016 USPSTF guideline “Statin use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication”.

Finally, for history buffs interested in a brief history of the discovery and development of this drug class, please see this paper by Akira Endo.

References / Additional Reading:
1. 4S @ Wiki JournalClub
2. “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults”
3. “Statin use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication” (2016)
4. UpToDate, “Society guideline links: Lipid disorders in adults”
5. “A historical perspective on the discovery of statins” (2010)

Summary by Duncan F. Moore, MD

Image Credit: Siol, CC BY-SA 3.0, via Wikimedia Commons

Week 15 – CHADS2

“Validation of Clinical Classification Schemes for Predicting Stroke”

JAMA. 2001 June 13;285(22):2864-70. [free full text]

Atrial fibrillation is the most common cardiac arrhythmia and affects 1-2% of the overall population with increasing prevalence as people age. Atrial fibrillation also carries substantial morbidity and mortality due to the risk of stroke and thromboembolism although the risk of embolic phenomenon varies widely across various subpopulations. In 2001, the only oral anticoagulation options available were warfarin and aspirin, which had relative risk reductions of 62% and 22%, respectively, consistent across these subpopulations. Clinicians felt that high risk patients should be anticoagulated, but the two common classification schemes, AFI and SPAF, were flawed. Patients were often classified as low risk in one scheme and high risk in the other. The schemes were derived retrospectively and were clinically ambiguous. Therefore, in 2001, a group of investigators combined the two existing schemes to create the CHADS2 scheme and applied it to a new data set.

Population (NRAF cohort): Hospitalized Medicare patients ages 65-95 with non-valvular AF not prescribed warfarin at hospital discharge.

Intervention: Determination of CHADS2 score (1 point for recent CHF, hypertension, age ≥ 75, and DM; 2 points for a history of stroke or TIA)

Comparison: AFI and SPAF risk schemes

Measured Outcome: Hospitalization rates for ischemic stroke (per ICD-9 codes from Medicare claims), stratified by CHADS2 / AFI / SPAF scores.

Calculated Outcome: performance of the various schemes, based on c statistic (a measure of predictive accuracy in a binary logistic regression model)

1733 patients were identified in the NRAF cohort. When compared to the AFI and SPAF trials, these patients tended be older (81 in NRAF vs. 69 in AFI vs. 69 in SPAF), have a higher burden of CHF (56% vs. 22% vs. 21%), are more likely to be female (58% vs. 34% vs. 28%), and have a history of DM (23% vs. 15% vs. 15%) or prior stroke/TIA (25% vs. 17% vs. 8%). The stroke rate was lowest in the group with a CHADS2 = 0 (1.9 per 100 patient years, adjusting for the assumption that aspirin was not taken). The stroke rate increased by a factor of approximately 1.5 for each 1-point increase in the CHADS2 score.

CHADS2 score           NRAF Adjusted Stroke Rate per 100 Patient-Years
0                                      1.9
1                                      2.8
2                                      4.0
3                                      5.9
4                                      8.5
5                                      12.5
6                                      18.2

The CHADS2 scheme had a c statistic of 0.82 compared to 0.68 for the AFI scheme and 0.74 for the SPAF scheme.

The CHADS2 scheme provides clinicians with a scoring system to help guide decision making for anticoagulation in patients with non-valvular AF.

The authors note that the application of the CHADS2 score could be useful in several clinical scenarios. First, it easily identifies patients at low risk of stroke (CHADS2 = 0) for whom anticoagulation with warfarin would probably not provide significant benefit. The authors argue that these patients should merely be offered aspirin. Second, the CHADS2 score could facilitate medication selection based on a patient-specific risk of stroke. Third, the CHADS2 score could help clinicians make decisions regarding anticoagulation in the perioperative setting by evaluating the risk of stroke against the hemorrhagic risk of the procedure. Although the CHADS2 is no longer the preferred risk-stratification scheme, the same concepts are still applicable to the more commonly used CHA2DS2-VASc.

This study had several strengths. First, the cohort was from seven states that represented all geographic regions of the United States. Second, CHADS2 was pre-specified based on previous studies and validated using the NRAF data set. Third, the NRAF data set was obtained from actual patient chart review as opposed to purely from an administrative database. Finally, the NRAF patients were older and sicker than those of the AFI and SPAF cohorts, and thus the CHADS2 appears to be generalizable to the very large demographic of frail, elderly Medicare patients.

As CHADS2 became widely used clinically in the early 2000s, its application to other cohorts generated a large intermediate-risk group (CHADS2 = 1), which was sometimes > 60% of the cohort (though in the NRAF cohort, CHADS2 = 1 accounted for 27% of the cohort). In clinical practice, this intermediate-risk group was to be offered either warfarin or aspirin. Clearly, a clinical-risk predictor that does not provide clear guidance in over 50% of patients needs to be improved. As a result, the CHA2DS2-VASc scoring system was developed from the Birmingham 2009 scheme. When compared head-to-head in registry data, CHA2DS2-VASc more effectively discriminated stroke risk among patients with a baseline CHADS2 score of 0 to 1. Because of this, CHA2DS2-VASc is the recommended risk stratification scheme in the AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation. In modern practice, anticoagulation is unnecessary when CHA2DS2-VASc score = 0, should be considered (vs. antiplatelet or no treatment) when score = 1, and is recommended when score ≥ 2.

Further Reading:
1. AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation
2. CHA2DS2-VASc (2010)
3. 2 Minute Medicine

Summary by Ryan Commins, MD

Image Credit: Alisa Machalek, NIGMS/NIH – National Insititue of General Medical Sciences, Public Domain

Week 11 – AFFIRM

“A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation”

by the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators

N Engl J Med. 2002 Dec 5;347(23):1825-33. [free full text]

It seems like the majority of patients with atrial fibrillation that we encounter today in the inpatient setting are being treated with a rate-control strategy, as opposed to a rhythm-control strategy. There was a time when both approaches were considered acceptable, and perhaps rhythm control was even the preferred initial strategy. The AFFIRM trial was the landmark study to address this debate.

The trial randomized patients with atrial fibrillation (judged “likely to be recurrent”) aged 65 or older “or who had other risk factors for stroke or death” to either 1) a rhythm-control strategy with one or more drugs from a pre-specified list and/or cardioversion to achieve sinus rhythm or 2) a rate-control strategy with beta-blockers, CCBs, and/or digoxin to a target resting HR ≤ 80 and a six-minute walk test HR ≤ 110. The primary endpoint was death during follow-up. The major secondary endpoint was a composite of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, and cardiac arrest.

4060 patients were randomized. Death occurred in 26.7% of rhythm-control patients versus 25.9% of rate-control patients (HR 1.15, 95% CI 0.99 – 1.34, p = 0.08). The composite secondary endpoint occurred in 32.0% of rhythm control-patients versus 32.7% of rate-control patients (p = 0.33). Rhythm-control strategy was associated with a higher risk of death among patients older than 65 and patients with CAD (see Figure 2). Additionally, rhythm-control patients were more likely to be hospitalized during follow-up (80.1% vs. 73.0%, p < 0.001) and to develop torsades de pointes (0.8% vs. 0.2%, p = 0.007).

This trial demonstrated that a rhythm-control strategy in atrial fibrillation offers no mortality benefit over a rate-control strategy. At the time of publication, the authors wrote that rate control was an “accepted, though often secondary alternative” to rhythm control. Their study clearly demonstrated that there was no significant mortality benefit to either strategy and that hospitalizations were greater in the rhythm-control group. In subgroup analysis that rhythm control led to higher mortality among the elderly and those with CAD. Notably, 37.5% of rhythm-control patients had crossed over to rate control strategy by 5 years of follow-up, whereas only 14.9% of rate-control patients had switched over to rhythm control.

But what does this study mean for our practice today? Generally speaking, rate control is preferred in most patients, particularly the elderly and patients with CHF, whereas rhythm control may be pursued in patients with persistent symptoms despite rate control, patients unable to achieve rate control on AV nodal agents alone, and patients younger than 65. Both the AHA/ACC (2014) and the European Society of Cardiology (2016) guidelines have extensive recommendations that detail specific patient scenarios.

Further Reading / References:
1. Cardiologytrials.org
2. Wiki Journal Club
3. 2 Minute Medicine
4. Visual abstract @ Visualmed

Summary by Duncan F. Moore, MD

Image Credit: Drj via Wikimedia Commons

Week 6 – SOLVD

“Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure”

by the Studies of Left Ventricular Dysfunction (SOLVD) Investigators

N Engl J Med. 1991 Aug 1;325(5):293-302. [free full text]

Heart failure with reduced ejection fraction (HFrEF) is a very common and highly morbid condition. We now know that blockade of the renin-angiotensin-aldosterone system (RAAS) with an ACEi or ARB is a cornerstone of modern HFrEF treatment. The 1991 SOLVD trial played an integral part in demonstrating the benefit of and broadening the indication for RAAS blockade in HFrEF.

The trial enrolled patients with HFrEF and LVEF ≤ 35% who were already on treatment (but not on an ACEi) and had Cr ≤ 2.0 and randomized them to treatment with enalapril BID (starting at 2.5mg and uptitrated as tolerated to 20mg BID) or treatment with placebo BID (again, starting at 2.5mg and uptitrated as tolerated to 20mg BID). Of note, there was a single-blind run-in period with enalapril in all patients, followed by a single-blind placebo run-in period. Finally, the patient was randomized to his/her actual study drug in a double-blind fashion. The primary outcomes were all-cause mortality and death from or hospitalization for CHF. Secondary outcomes included hospitalization for CHF, all-cause hospitalization, cardiovascular mortality, and CHF-related mortality.

2569 patients were randomized. Follow-up duration ranged from 22 to 55 months. 510 (39.7%) placebo patients died during follow-up compared to 452 (35.2%) enalapril patients (relative risk reduction of 16% per log-rank test, 95% CI 5-26%, p = 0.0036). See Figure 1 for the relevant Kaplan-Meier curves. 736 (57.3%) placebo patients died or were hospitalized for CHF during follow-up compared to 613 (47.7%) enalapril patients (relative risk reduction 26%, 95% CI 18-34, p < 0.0001). Hospitalizations for heart failure, all-cause hospitalizations, cardiovascular deaths, and deaths due to heart failure were all significantly reduced in the enalapril group. 320 placebo patients discontinued the study drug versus only 182 patients in the enalapril group. Enalapril patients were significantly more likely to report dizziness, fainting, and cough. There was no difference in the prevalence of angioedema.

Treatment of HFrEF with enalapril significantly reduced mortality and hospitalizations for heart failure. The authors note that for every 1000 study patients treated with enalapril, approximately 50 premature deaths and 350 heart failure hospitalizations were averted. The mortality benefit of enalapril appears to be immediate and increases for approximately 24 months. Per the authors, “reductions in deaths and rates of hospitalization from worsening heart failure may be related to improvements in ejection fraction and exercise capacity, to a decrease in signs and symptoms of congestion, and also to the known mechanism of action of the agent – i.e., a decrease in preload and afterload when the conversion of angiotensin I to angiotensin II is blocked.” Strengths of this study include its double-blind, randomized design, large sample size, and long follow-up. The fact that the run-in period allowed for the exclusion prior to randomization of patients who did not immediately tolerate enalapril is a major limitation of this study.

Prior to SOLVD, studies of ACEi in HFrEF had focused on patients with severe symptoms. The 1987 CONSENSUS trial was limited to patients with NYHA class IV symptoms. SOLVD broadened the indication of ACEi treatment to a wider group of symptoms and correlating EFs. Per the current 2013 ACCF/AHA guidelines for the management of heart failure, ACEi/ARB therapy is a Class I recommendation in all patients with HFrEF in order to reduce morbidity and mortality.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Effects of enalapril on mortality in severe congestive heart failure – Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). 1987.
4. 2013 ACCF/AHA guideline for the management of heart failure: executive summary

Summary by Duncan F. Moore, MD

Week 1 – CAST

“Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo”

The Cardiac Arrhythmia Suppression Trial (CAST)

N Engl J Med. 1991 Mar 21;324(12):781-8. [free full text]

Ventricular arrhythmias are common following MI, and studies have demonstrated that PVCs and other arrhythmias such as non-sustained ventricular tachycardia (NSVT) are independent risk factors for cardiac mortality following MI. As such, by the late 1980s, many patients with PVCs post-MI were treated with antiarrhythmic drugs in an attempt to reduce mortality. The 1991 CAST trial sought to prove what predecessor trials had failed to prove – that suppression of such rhythms post-MI would improve survival.

This trial took post-MI patients with PVCs (with no sustained VT) and reduced EF and randomized them to an open-label titration period in which encainide, flecainide, or moricizine was titrated to suppress at least 80% of the PVCs and 90% of the runs of NSVT. Patients were then either randomized to continuation of the antiarrhythmic drug assigned during the titration period or transitioned to a placebo. The primary outcome was death or cardiac arrest with resuscitation, “either of which was due to arrhythmia.”

The trial was terminated early due to increased mortality in the encainide and flecainide treatment groups. 1498 patients were randomized following successful titration during the open-label period, and they were reported in this paper. The results of the moricizine arm were reported later in a different paper (CAST-II). The RR of death or cardiac arrest due to arrhythmia was 2.64 (95% CI 1.60–4.36; number needed to harm = 28.2). See Figure 1 on page 783 for a striking Kaplan-Meier curve. The RR of death or cardiac arrest due to all causes was 2.38 (95% CI 1.59–3.57; NNH = 20.6). Regarding other secondary outcomes, cardiac death/arrest due to any cardiac cause was similarly elevated in the treatment group, and there were no significant differences in non-lethal endpoints among the treatment and placebo arms.

In this large RCT, the treatment of asymptomatic ventricular arrhythmias with encainide and flecainide in patients with LV dysfunction following MI resulted in increased mortality. This study provides a classic example of how a treatment that seems to make intuitive sense based on observational data can be easily and definitively disproven with a placebo-controlled trial with hard endpoints (e.g. death). Although PVCs and NSVT are associated with cardiac death post-MI and reducing these arrhythmias might seem like an intuitive strategy for reducing death, correlation does not equal causation. Modern expert opinion at UpToDate notes no role for suppression of asymptomatic PVCs or NSVT in the peri-infarct period. Indeed such suppression may increase mortality. As noted on Wiki Journal Club, modern ACC/AHA guidelines “do not comment on the use of antiarrhythmic medications in ACS care.”

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. CAST-I Trial @ ClinicalTrials.gov
4. CAST-II trial publication, NEJM 1992
5. UpToDate “Clinical features and treatment of ventricular arrhythmias during acute myocardial infarction”

Summary by Duncan F. Moore, MD

Image Credit: By CardioNetworks: Drj – CardioNetworks: Nsvt.png, CC BY-SA 3.0

Week 48 – HAS-BLED

“A Novel User-Friendly Score (HAS-BLED) To Assess 1-Year Risk of Major Bleeding in Patients with Atrial Fibrillation”

Chest. 2010 Nov;138(5):1093-100. [free full text]

Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke. Stroke risk is further increased by individual comorbidities such as CHF, HTN, and DM and can be stratified with scores such as CHADS2 and CHA2DS2VASC. The recommendation for patients with intermediate stroke risk is treatment with oral anticoagulation (OAC). However, stroke risk is often closely related to bleeding risk, and the benefits of anticoagulation for stroke need to be weighed against the added risk of bleeding. At the time of this study, there were no validated and user-friendly bleeding risk-stratification schemes. This study aimed to develop a practical risk score to estimate the 1-year risk of major bleeding (as defined in the study) in a contemporary, real-world cohort of patients with AF.

Population: adults with EKG or Holter-proven diagnosis of AF
Exclusion criteria: mitral valve stenosis, valvular surgery

(Patients were identified from the prospectively developed database of the multi-center Euro Heart Survey on AF. Among 5,272 patients with AF, 3,456 were free of mitral valve stenosis or valve surgery and completed their 1-year follow-up assessment.)

No experiment was performed in this retrospective cohort study.

In a derivation cohort, the authors retrospectively performed univariate analyses to identify a range of clinical features associated with major bleeding (p < 0.10). Based on systematic reviews, they added additional risk factors for major bleeding. Ultimately, the result was a list of comprehensive risk factors that make up the acronym HAS-BLED:

H – Hypertension (> 160 mmHg systolic)
A – Abnormal renal (HD, transplant, Cr > 2.26 mg/dL) and liver function (cirrhosis, bilirubin >2x normal w/ AST/ALT/ALP > 3x normal) – 1 pt each for abnormal renal or liver function
S – Stroke

B – Bleeding (prior major bleed or predisposition to bleed)
L – Labile INRs (time in therapeutic range < 60%)
E – Elderly (age > 65)
D – Drugs (i.e. ASA, clopidogrel, NSAIDs) or alcohol use (> 8 units per week) concomitantly – 1 pt each for use of either

Each risk factor represents one point each. The HAS-BLED score was then compared to the HEMORR2HAGES scheme, a previously developed tool for estimating bleeding risk.


  • incidence of major bleeding within 1 year
  • bleeds per 100 patient-years, stratified by HAS-BLED score
  • c-statistic for the HAS-BLED score in predicting the risk of bleeding


  • major bleeding: bleeding causing hospitalization, Hgb drop >2 g/L, or bleeding requiring blood transfusion (excluded hemorrhagic stroke)
  • hemorrhagic stroke: focal neurologic deficit of sudden onset that is diagnosed by a neurologist, lasting > 24h, and caused by bleeding

3,456 AF patients (without mitral valve stenosis or valve surgery) who completed their 1-year follow-up were analyzed retrospectively. 64.8% (2242) of these patients were on OAC (with 12.8% (286) of this subset on concurrent antiplatelet therapy), 24% (828) were on antiplatelet therapy alone, and 10.2% (352) received no antithrombotic therapy. 1.5% (53) of patients experienced a major bleed during the first year. 17% (9) of these patients sustained intracerebral hemorrhage.

HAS-BLED Score       Bleeds per 100-patient years
0                                        1.13
1                                         1.02
2                                        1.88
3                                        3.74
4                                        8.70
5                                        12.50
6*                                     0.0                   *(n = 2 patients at risk, neither bled)

Patients were given a HAS-BLED score and a HEMORR2HAGES score. C-statistics were then used to determine the predictive accuracy of each model overall as well as within patient subgroups (OAC alone, OAC + antiplatelet, antiplatelet alone, and no antithrombotic therapy).

C statistics for HAS-BLED:
For overall cohort, 0.72 (95% CI 0.65-0.79); for OAC alone, 0.69 (95% CI 0.59-0.80); for OAC + antiplatelet, 0.78 (95% CI 0.65-0.91); for antiplatelet alone, 0.91 (95% CI 0.83-1.00); and for those on no antithrombotic therapy, 0.85 (95% CI 0.00-1.00).

C statistics for HEMORR2HAGES:
For overall cohort, 0.66 (95% CI 0.57-0.74); for OAC alone, 0.64 (95% CI 0.53-0.75); for OAC + antiplatelet, 0.83 (95% CI 0.74-0.91); for antiplatelet alone, 0.83 (95% CI 0.68-0.98); and for those on no antithrombotic therapy, 0.81 (95% CI 0.00-1.00).

This study helped to establish a practical and user-friendly assessment of bleeding risk in AF. HAS-BLED is superior to its predecessor HEMORR2HAGES because the acronym is easier to remember, the assessment is quicker and simpler to perform, and all risk factors are readily available from the clinical history or routine testing. Both stratification tools had (grossly) similar c-statistics for the overall cohort – 0.72 for HAS-BLED versus 0.66 for HEMORR2HAGES. However, HAS-BLED was particularly useful when looking at antiplatelet therapy alone or no antithrombotic therapy at all (0.91 and 0.85, respectively).

This study is useful because it provides evidence-based, easily calculable, and actionable risk stratification in the assessment of bleeding risk in AF. In prior studies, such as ACTIVE-A (ASA + clopidogrel versus ASA alone for patients with AF deemed unsuitable for OAC), almost half of all patients (n= ~3500) were given a classification of “unsuitable for OAC,” which was based solely on physicians’ clinical judgement without a predefined objective scoring. Now, physicians have an objective way to assess bleed risk rather than “gut feeling” or wanting to avoid iatrogenic insult.

The RE-LY trial used the HAS-BLED score to decide which patients with AF should get the standard dabigatran dose (150mg BID) rather than a lower dose (110mg BID) for anticoagulation. This risk-stratified dosing resulted in a significant reduction in major bleeding compared with warfarin but maintained a similar reduction in stroke risk.

Furthermore, the HAS-BLED score could allow the physician to be more confident when deciding which patients may be appropriate for referral for a left atrial appendage occlusion device (e.g. Watchman).

The study had a limited number of major bleeds and a short follow-up period, and thus it is possible that other important risk factors for bleeding were not identified. Also, there were large numbers of patients lost to 1-year follow-up. These patients likely had more comorbidities and may have transferred to nursing homes or even died. Their loss to follow-up and thus exclusion from this retrospective study may have led to an underestimate of true bleeding rates. Furthermore, generalizability is limited by the modest number of very elderly patients (i.e. 75-84 and ≥85), who likely represent the greatest bleeding risk. Finally, this study did not specify what proportion of its patients were on warfarin for their OAC, but given that dabigatran, rivaroxaban, and apixaban were not yet approved for use in Europe (2008, 2008, and 2011, respectively) for the majority of the study, we can assume most patients were on warfarin. Thus the generalizability of HAS-BLED risk stratification to the DOACs is limited.

Bottom Line:
HAS-BLED provides an easy, practical tool to assess the individual bleeding risk of patients with AF. Oral anticoagulation should be considered for scores of 3 or less. If HAS-BLED scores are ≥4, it is reasonable to think about alternatives to oral anticoagulation.

Further Reading/References:
1. 2 Minute Medicine
2. ACTIVE-A trial
3. RE-LY trial
4. RE-LY @ Wiki Journal Club
5. HAS-BLED Calculator
6. HEMORR2HAGES Calculator
7. Watchman (for Healthcare Professionals)

Summary by Patrick Miller, MD