Week 19 – 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 12 – 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

Week 16 – National Lung Screening Trial (NLST)

“Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening”

by the National Lung Cancer Screening Trial (NLST) Research Team

N Engl J Med. 2011 Aug 4;365(5):395-409 [free full text]

Despite a reduction in smoking rates in the United States, lung cancer remains the number one cause of cancer death in the United States as well as worldwide. Earlier studies of plain chest radiography for lung cancer screening demonstrated no benefit, and in 2002 the National Lung Screening Trial (NLST) was undertaken to determine whether then recent advances in CT technology could lead to an effective lung cancer screening method.

The study enrolled adults age 55-74 with 30+ pack-years of smoking (if former smokers, they must have quit within the past 15 years). Patients were randomized to either the intervention of three annual screenings for lung cancer with low-dose CT or to the comparator/control group to receive three annual screenings for lung cancer with PA chest radiograph. The primary outcome was mortality from lung cancer. Notable secondary outcomes were all-cause mortality and the incidence of lung cancer.

53,454 patients were randomized, and both groups had similar baseline characteristics. The low-dose CT group sustained 247 deaths from lung cancer per 100,000 person-years, whereas the radiography group sustained 309 deaths per 100,000 person-years. A relative reduction in rate of death by 20.0% was seen in the CT group (95% CI 6.8 – 26.7%, p = 0.004). The number needed to screen with CT to prevent one lung cancer death was 320. There were 1877 deaths from any cause in the CT group and 2000 deaths in the radiography group, so CT screening demonstrated a risk reduction of death from any cause of 6.7% (95% CI 1.2% – 13.6%, p = 0.02). Incidence of lung cancer in the CT group was 645 per 100,000 person-years and 941 per 100,000 person-years in the radiography group (RR 1.13, 95% CI 1.03 – 1.23).

Lung cancer screening with low-dose CT scan in high-risk patients provides a significant mortality benefit. This trial was stopped early because the mortality benefit was so high. The benefit was driven by the reduction in deaths attributed to lung cancer, and when deaths from lung cancer were excluded from the overall mortality analysis, there was no significant difference among the two arms. Largely on the basis of this study, the 2013 USPSTF guidelines for lung cancer screening recommend annual low-dose CT scan in patients who meet NLST inclusion criteria. However, it must be noted that, even in the “ideal” circumstances of this trial performed at experienced centers, 96% of abnormal CT screening results in this trial were actually false positives. Of all positive results, 11% led to invasive studies.

Per UpToDate, since NSLT, there have been several European low-dose CT screening trials published. However, all but one (NELSON) appear to be underpowered to demonstrate a possible mortality reduction. Meta-analysis of all such RCTs could allow for further refinement in risk stratification, frequency of screening, and management of positive screening findings.

No randomized trial has ever demonstrated a mortality benefit of plain chest radiography for lung cancer screening. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial tested this modality vs. “community care,” and because the PLCO trial was ongoing at the time of creation of the NSLT, the NSLT authors trial decided to compare their intervention (CT) to plain chest radiography in case the results of plain chest radiography in PLCO were positive. Ultimately, they were not.

Further Reading:
1. USPSTF Guidelines for Lung Cancer Screening (2013)
2. NLST @ ClinicalTrials.gov
3. NLST @ Wiki Journal Club
4. NLST @ 2 Minute Medicine
5. UpToDate, “Screening for lung cancer”

Summary by Duncan F. Moore, MD

Image Credit: Yale Rosen, CC BY-SA 2.0, via Wikimedia Commons

Week 14 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]

Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had addressed definitively whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

This trial randomized patients with T2DM, hypertension, and nephropathy (per proteinuria and elevated Cr) to treatment with either irbesartan, amlodipine, or placebo. The drug in each arm was titrated to achieve a target SBP ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed. The primary outcome was a composite of the doubling of serum Cr, onset of ESRD, or all-cause mortality. Secondary outcomes included individual components of the primary outcome and a composite cardiovascular outcome.

1715 patients were randomized. The mean blood pressure after the baseline visit was 140/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons of MAP between irbesartan or amlodipine and placebo). Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine. The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups. There were no significant group differences with respect to the composite cardiovascular outcome. Importantly, a sensitivity analysis was performed which demonstrated that the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

In summary, irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering. This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint. The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.” In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy. This trial was published concurrently in NEJM with the RENAAL trial [https://www.wikijournalclub.org/wiki/RENAAL]. RENAAL was a similar trial of losartan vs. placebo in T2DM and demonstrated a similar reduction in the doubling of serum creatinine as well as a 28% reduction in progression to ESRD. In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes. Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.

Further Reading/References:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

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

Week 13 – VERT

“Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis”

by the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group

JAMA. 1999 Oct 13;282(14):1344-52. [free full text]

Bisphosphonates are a highly effective and relatively safe class of medications for the prevention of fractures in patients with osteoporosis. The VERT trial published in 1999 was a landmark trial that demonstrated this protective effect with the daily oral bisphosphonate risedronate.

The trial enrolled post-menopausal women with either 2 or more vertebral fractures per radiography or 1 vertebral fracture with decreased lumbar spine bone mineral density. Patients were randomized to the treatment arm (risedronate 2.5mg PO daily or risedronate 5mg PO daily) to the daily PO placebo control arm. Measured outcomes included: 1) the prevalence of new vertebral fracture at 3 years follow-up, per annual imaging, 2) the prevalence of new non-vertebral fracture at 3 years follow-up, per annual imaging, and 3) change in bone mineral density, per DEXA q6 months.

2458 patients were randomized. During the course of the study, “data from other trials indicated that the 2.5mg risedronate dose was less effective than the 5mg dose,” and thus the authors discontinued further data collection on the 2.5mg treatment arm at 1 year into the study. All treatment groups had similar baseline characteristics. 55% of the placebo group and 60% of the 5mg risedronate group completed 3 years of treatment. The prevalence of new vertebral fracture within 3 years was 11.3% in the risedronate group and 16.3% in the placebo group (RR 0.59, 95% CI 0.43-0.82, p = 0.003; NNT = 20). The prevalence of new non-vertebral fractures at 3 years was 5.2% in the treatment arm and 8.4% in the placebo arm (RR 0.6, 95% CI 0.39-0.94, p = 0.02; NNT = 31). Regarding bone mineral density (BMD), see Figure 4 for a visual depiction of the changes in BMD by treatment group at the various 6-month timepoints. Notably, change from baseline BMD of the lumbar spine and femoral neck was significantly higher (and positive) in the risedronate 5mg group at all follow-up timepoints relative to the placebo group and at all timepoints except 6 months for the femoral trochanter measurements. Regarding adverse events, there was no difference in the incidence of upper GI adverse events among the two groups. GI complaints “were the most common adverse events associated with study discontinuance,” and GI events lead to 42% of placebo withdrawals but only 36% of the 5mg risedronate withdrawals.

Oral risedronate reduces the risk of vertebral and non-vertebral fractures in patients with osteoporosis while increasing bone mineral density. Overall, this was a large, well-designed RCT that demonstrated a concrete treatment benefit. As a result, oral bisphosphonate therapy has become the standard of care both for treatment and prevention of osteoporosis. This study, as well as others, demonstrated that such therapies are well-tolerated with relatively few side effects. A notable strength of this study is that it did not exclude patients with GI comorbidities.  One weakness is the modification of the trial protocol to eliminate the risedronate 2.5mg treatment arm after 1 year of study. Although this arm demonstrated a reduction in vertebral fracture at 1 year relative to placebo (p = 0.02), its elimination raises suspicion that the pre-specified analyses were not yielding the anticipated results during the interim analysis and thus the less-impressive treatment arm was discarded.

Further Reading/References:
1. Weekly alendronate vs. weekly risedronate
2. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review (2014)

Summary by Duncan F. Moore, MD

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

Week 11 – Varenicline vs. Bupropion and Placebo for Smoking Cessation

“Varenicline, an α2β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation”

JAMA. 2006 Jul 5;296(1):56-63. [free full text]

Assisting our patients in smoking cessation is a fundamental aspect of outpatient internal medicine. At the time of this trial, the only approved pharmacotherapies for smoking cessation were nicotine replacement therapy and bupropion. As the α2β2 nicotinic acetylcholine receptor (nAChR) was thought to be crucial to the reinforcing effects of nicotine, it was hypothesized that a partial agonist for this receptor could yield sufficient effect to satiate cravings and minimize withdrawal symptoms but also limit the reinforcing effects of exogenous nicotine. Thus Pfizer designed this large phase 3 trial to test the efficacy of its new α2β2 nAChR partial agonist varenicline (Chantix) against the only other non-nicotine pharmacotherapy at the time (bupropion) as well as placebo.

The trial enrolled adult smokers (10+ cigarettes per day) with fewer than three months of smoking abstinence in the past year (notable exclusion criteria included numerous psychiatric and substance use comorbidities). Patients were randomized to 12 weeks of treatment with either varenicline uptitrated by day 8 to 1mg BID, bupropion SR uptitrated by day 4 to 150mg BID, or placebo BID. Patients were also given a smoking cessation self-help booklet at the index visit and encouraged to set a quit date of day 8. Patients were followed at weekly clinic visits for the first 12 weeks (treatment duration) and then a mixture of clinic and phone visits for weeks 13-52. Non-smoking status during follow-up was determined by patient self-report combined with exhaled carbon monoxide < 10ppm. The primary endpoint was the 4-week continuous abstinence rate for study weeks 9-12 (as confirmed by exhaled CO level). Secondary endpoints included the continuous abstinence rate for weeks 9-24 and for weeks 9-52.

1025 patients were randomized. Compliance was similar among the three groups and the median duration of treatment was 84 days. Loss to follow-up was similar among the three groups. CO-confirmed continuous abstinence during weeks 9-12 was 44.0% among the varenicline group vs. 17.7% among the placebo group (OR 3.85, 95% CI 2.70–5.50, p < 0.001) vs. 29.5% among the bupropion group (OR vs. varenicline group 1.93, 95% CI 1.40–2.68, p < 0.001). (OR for bupropion vs. placebo was 2.00, 95% CI 1.38–2.89, p < 0.001.) Continuous abstinence for weeks 9-24 was 29.5% among the varenicline group vs. 10.5% among the placebo group (p < 0.001) vs. 20.7% among the bupropion group (p = 0.007). Continuous abstinence rates weeks 9-52 were 21.9% among the varenicline group vs. 8.4% among placebo group (p < 0.001) vs. 16.1% among the bupropion group (p = 0.057). Subgroup analysis of the primary outcome by sex did not yield significant differences in drug efficacy by sex.

This study demonstrated that varenicline was superior to both placebo and bupropion in facilitating smoking cessation at up to 24 weeks. At greater than 24 weeks, varenicline remained superior to placebo but was similarly efficacious as bupropion. This was a well-designed and executed large, double-blind, placebo- and active-treatment-controlled multicenter US trial. The trial was completed in April 2005 and a new drug application for varenicline (Chantix) was submitted to the FDA in November 2005. Of note, an “identically designed” (per this study’s authors), manufacturer-sponsored phase 3 trial was performed in parallel and reported very similar results in the in the same July 2006 issue of JAMA (PMID: 16820547) as the above study by Gonzales et al. These robust, positive-outcome pre-approval trials of varenicline helped the drug rapidly obtain approval in May 2006.

Per expert opinion at UpToDate, varenicline remains a preferred first-line pharmacotherapy for smoking cessation. Bupropion is a suitable, though generally less efficacious, alternative, particularly when the patient has comorbid depression. Per UpToDate, the recent (2016) EAGLES trial demonstrated that “in contrast to earlier concerns, varenicline and bupropion have no higher risk of associated adverse psychiatric effects than [nicotine replacement therapy] in smokers with comorbid psychiatric disorders.”

Further Reading/References:
1. This trial @ ClinicalTrials.gov
2. Sister trial: “Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial.” JAMA. 2006 Jul 5;296(1):56-63.
3. Chantix FDA Approval Letter 5/10/2006
4. Rigotti NA. Pharmacotherapy for smoking cessation in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc.
5. “Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.” Lancet. 2016 Jun 18;387(10037):2507-20.
6. 2 Minute Medicine: “Varenicline and bupropion more effective than varenicline alone for tobacco abstinence”
7. 2 Minute Medicine: “Varenicline safe for smoking cessation in patients with stable major depressive disorder”

Summary by Duncan F. Moore, MD

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

Week 50 – VERT

“Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis”

by the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group

JAMA. 1999 Oct 13;282(14):1344-52. [free full text]

Bisphosphonates are a highly effective and relatively safe class of medications for the prevention of fractures in patients with osteoporosis. The VERT trial published in 1999 was a landmark trial that demonstrated this protective effect with the daily oral bisphosphonate risedronate.

The trial enrolled post-menopausal women with either 2 or more vertebral fractures per radiography or 1 vertebral fracture with decreased lumbar spine bone mineral density. Patients were randomized to the treatment arm (risedronate 2.5mg PO daily or risedronate 5mg PO daily) to the daily PO placebo control arm. Measured outcomes included: 1) the prevalence of new vertebral fracture at 3 years follow-up, per annual imaging, 2) the prevalence of new non-vertebral fracture at 3 years follow-up, per annual imaging, and 3) change in bone mineral density, per DEXA q6 months.

2458 patients were randomized. During the course of the study, “data from other trials indicated that the 2.5mg risedronate dose was less effective than the 5mg dose,” and thus the authors discontinued further data collection on the 2.5mg treatment arm at 1 year into the study. All treatment groups had similar baseline characteristics. 55% of the placebo group and 60% of the 5mg risedronate group completed 3 years of treatment. The prevalence of new vertebral fracture within 3 years was 11.3% in the risedronate group and 16.3% in the placebo group (RR 0.59, 95% CI 0.43-0.82, p = 0.003; NNT = 20). The prevalence of new non-vertebral fractures at 3 years was 5.2% in the treatment arm and 8.4% in the placebo arm (RR 0.6, 95% CI 0.39-0.94, p = 0.02; NNT = 31). Regarding bone mineral density (BMD), see Figure 4 for a visual depiction of the changes in BMD by treatment group at the various 6-month timepoints. Notably, change from baseline BMD of the lumbar spine and femoral neck was significantly higher (and positive) in the risedronate 5mg group at all follow-up timepoints relative to the placebo group and at all timepoints except 6 months for the femoral trochanter measurements. Regarding adverse events, there was no difference in the incidence of upper GI adverse events among the two groups. GI complaints “were the most common adverse events associated with study discontinuance,” and GI events lead to 42% of placebo withdrawals but only 36% of the 5mg risedronate withdrawals.

Oral risedronate reduces the risk of vertebral and non-vertebral fractures in patients with osteoporosis while increasing bone mineral density. Overall, this was a large, well-designed RCT that demonstrated a concrete treatment benefit. As a result, oral bisphosphonate therapy has become the standard of care both for treatment and prevention of osteoporosis. This study, as well as others, demonstrated that such therapies are well-tolerated with relatively few side effects. A notable strength of this study is that it did not exclude patients with GI comorbidities.  One weakness is the modification of the trial protocol to eliminate the risedronate 2.5mg treatment arm after 1 year of study. Although this arm demonstrated a reduction in vertebral fracture at 1 year relative to placebo (p = 0.02), its elimination raises suspicion that the pre-specified analyses were not yielding the anticipated results during the interim analysis and thus the less-impressive treatment arm was discarded.

Further Reading/References:
1. Weekly alendronate vs. weekly risedronate [https://www.ncbi.nlm.nih.gov/pubmed/15619680]
2. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review (2014) [https://www.ncbi.nlm.nih.gov/pubmed/25199883]

Summary by Duncan F. Moore, MD

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

Week 48 – SYMPLICITY HTN-3

“A Controlled Trial of Renal Denervation for Resistant Hypertension”

N Engl J Med. 2014 Apr 10;370(15):1393-401 [free full text]

Approximately 10% of patients with hypertension have resistant hypertension (SBP > 140 despite adherence to three maximally tolerated doses of antihypertensives, including a diuretic). Evidence suggests that the sympathetic nervous system plays a large role in such cases, so catheter-based radiofrequency ablation of the renal arteries (renal denervation therapy) was developed as a potential treatment for resistant HTN. The 2010 SYMPLICITY HTN-2 trial was a small (n=106), non-blinded, randomized trial of renal denervation vs. continued care with oral antihypertensives that demonstrated a remarkable 30-mmHg greater decrease in SBP with renal denervation. Thus the 2014 SYMPLICITY HTN-3 trial was designed to evaluate the efficacy of renal denervation in a single-blinded trial with a sham-procedure control group.

The trial enrolled adults with resistant HTN with SBP ≥ 160 despite adherence to 3+ maximized antihypertensive drug classes, including a diuretic. (Pertinent exclusion criteria included secondary hypertension, renal artery stenosis > 50%, prior renal artery intervention.) Patients were randomized to either renal denervation with the Symplicity (Medtronic) radioablation catheter or to renal angiography only (sham procedure). The primary outcome was the mean change in office systolic BP from baseline at 6 months. (The examiner was blinded to intervention.) The secondary outcome was the change in mean 24-hour ambulatory SBP at 6 months. The primary safety endpoint was a composite of death, ESRD, embolic event with end-organ damage, renal artery or other vascular complication, hypertensive crisis within 30 days, or new renal artery stenosis of > 70%.

535 patients were randomized. On average, patients were receiving five antihypertensive medications. There was no significant difference in reduction of SBP between the two groups at 6 months. ∆SBP was -14.13 ± 23.93 mmHg in the denervation group vs. -11.74 ± 25.94 mmHg in the sham-procedure group for a between-group difference of -2.39 mmHg (95% CI -6.89 to 2.12, p = 0.26 with a superiority margin of 5 mmHg). The change in 24-hour ambulatory SBP at 6 months was -6.75 ± 15.11 mmHg in the denervation group vs. -4.79 ± 17.25 mmHg in the sham-procedure group for a between-group difference of -1.96 mmHg (95% CI -4.97 to 1.06, p = 0.98 with a superiority margin of 2 mmHg). There was no significant difference in the prevalence of the composite safety endpoint at 6 months with 4.0% of the denervation group and 5.8% of the sham-procedure group reaching the endpoint (percentage-point difference of -1.9, 95% CI -6.0 to 2.2).

In patients with resistant hypertension, renal denervation therapy provided no reduction in SBP at 6-month follow-up relative to a sham procedure.

This trial was an astounding failure for Medtronic and its Symplicity renal denervation radioablation catheter. The magnitude of the difference in results between the non-blinded, no-sham-procedure SYMPLICITY HTN-2 trial and this patient-blinded, sham-procedure-controlled trial is likely a product of 1) a marked placebo effect of procedural intervention, 2) Hawthorne effect in the non-blinded trial, and 3) regression toward the mean (patients were enrolled based on unusually high BP readings that over the course of the trial declined to reflect a lower true baseline).

Currently, there is no role for renal denervation therapy in the treatment of HTN (resistant or otherwise). However, despite the results of SYMPLICITY HTN-3, other companies and research groups are assessing the role of different radioablation catheters in patients with low-risk essential HTN and with resistant HTN. (For example, see https://www.ncbi.nlm.nih.gov/pubmed/29224639.)

Further Reading/References:
1. NephJC, SYMPLICITY HTN-3
2. UpToDate, “Treatment of resistant hypertension,” heading “Renal nerve denervation”

Summary by Duncan F. Moore, MD

Week 45 – COURAGE

“Optimal Medical Therapy with or without PCI for Stable Coronary Disease”

by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Research Group

N Engl J Med. 2007 Apr 12;356(15):1503-16 [free full text]

The optimal medical management of stable coronary artery disease has been well-described. However, prior to the 2007 COURAGE trial, the role of percutaneous coronary intervention (PCI) in the initial management of stable coronary artery disease was unclear. It was known that PCI improved angina symptoms and short-term exercise performance in stable disease, but its mortality benefit and reduction of future myocardial infarction and ACS were unknown.

The trial recruited patients with stable coronary artery disease. (See paper for inclusion/exclusion criteria. Disease had to be sufficiently and objectively severe, but not too severe, and symptoms could not be sustained at the highest CCS grade.) Patients were randomized to either optimal medical management (including antiplatelet, anti-anginal, ACEi/ARB, and cholesterol-lowering therapy) and PCI or to optimal medical management alone. The primary outcome was a composite of all-cause mortality and non-fatal MI.

2287 patients were randomized. Both groups had similar baseline characteristics with the exception of a higher prevalence of proximal LAD disease in the medical-therapy group. Median duration of follow-up was 4.6 years in both groups. Death or non-fatal MI occurred in 18.4% of the PCI group and in 17.8% of the medical-therapy group (p = 0.62). Death, non-fatal MI, or stroke occurred in 20.0% of the PCI group and 19.5% of the medical-therapy group (p = 0.62). Hospitalization for ACS occurred in 12.4% of the PCI group and 11.8% of the medical-therapy group (p = 0.56). Revascularization during follow-up was performed in 21.1% of the PCI group but in 32.6% of the medical-therapy group (HR 0.60, 95% CI 0.51–0.71, p < 0.001). Finally, 66% of PCI patients were free of angina at 1-year follow-up compared with 58% of medical-therapy patients (p < 0.001). Rates were 72% and 67% at 3 years (p = 0.02) and 72% and 74% at five years (not significant).

Thus, in the initial management of stable coronary artery disease, PCI in addition to optimal medical management provided no mortality benefit over optimal medical management alone. However, initial management with PCI did provide a time-limited improvement in angina symptoms.

As the authors of COURAGE nicely summarize on page 1512, the atherosclerotic plaques of ACS and stable CAD are different. Vulnerable, ACS-prone plaques have thin caps and spread outward along the wall of the coronary artery, as opposed to stable CAD plaques, which have thick fibrous caps and are associated with inward-directed remodeling that narrows the artery lumen (and cause reliable angina symptoms and luminal narrowing on coronary angiography).

Notable limitations of this study:

      • Generalizability was limited due to the population, which was largely male, white, and 42% came from VA hospitals.
      • Drug-eluting stents were not clinically available until the last 6 months of the study, so most stents placed were bare metal.

Later meta-analyses were weakly suggestive of an association of PCI with improved all-cause mortality. It is thought that there may be a subset of patients with stable CAD who achieve a mortality benefit from PCI.

The 2017 ORBITA trial made headlines and caused sustained controversy when it demonstrated in a randomized trial that, in the context of optimal medical therapy, PCI did not increase exercise time more than did a sham PCI. Take note of the relatively savage author’s reply to commentary regarding the trial. See blog discussion here. The ORBITA-2 trial is currently underway.

The ongoing ISCHEMIA trial is both eagerly awaited and involved in a degree of controversy after a recent change in endpoints.

It is important to note that all of the above discussions assume that the patient does not have specific coronary artery anatomy (e.g. left main disease, multi-vessel disease with decreased LVEF) in which initial CABG would provide a mortality benefit. Finally, PCI should be considered in patients whose physical activity is limited by angina symptoms despite optimal medical therapy.

Further Reading:
1. COURAGE @ Wiki Journal Club
2. COURAGE @ 2 Minute Medicine
3. Canadian Cardiovascular Society grading of angina pectoris
4. ORBITA-2 @ ClinicalTrials.gov
5. ISCHEMIA @ ClinicalTrials.gov
6. Discussion re: ISCHEMIA trial changes @ CardioBrief

Summary by Duncan F. Moore, MD

Image Credit: National Institutes of Health, US Public Domain, via Wikimedia Commons

Week 44 – National Lung Screening Trial (NLST)

“Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening”

by the National Lung Cancer Screening Trial (NLST) Research Team

N Engl J Med. 2011 Aug 4;365(5):395-409 [free full text]

Despite a reduction in smoking rates in the United States, lung cancer remains the number one cause of cancer death in the United States as well as worldwide. Earlier studies of plain chest radiography for lung cancer screening demonstrated no benefit, and in 2002 the National Lung Screening Trial (NLST) was undertaken to determine whether then recent advances in CT technology could lead to an effective lung cancer screening method.

The study enrolled adults age 55-74 with 30+ pack-years of smoking (if former smokers, they must have quit within the past 15 years). Patients were randomized to either the intervention of three annual screenings for lung cancer with low-dose CT or to the comparator/control group to receive three annual screenings for lung cancer with PA chest radiograph. The primary outcome was mortality from lung cancer. Notable secondary outcomes were all-cause mortality and the incidence of lung cancer.

53,454 patients were randomized, and both groups had similar baseline characteristics. The low-dose CT group sustained 247 deaths from lung cancer per 100,000 person-years, whereas the radiography group sustained 309 deaths per 100,000 person-years. A relative reduction in rate of death by 20.0% was seen in the CT group (95% CI 6.8 – 26.7%, p = 0.004). The number needed to screen with CT to prevent one lung cancer death was 320. There were 1877 deaths from any cause in the CT group and 2000 deaths in the radiography group, so CT screening demonstrated a risk reduction of death from any cause of 6.7% (95% CI 1.2% – 13.6%, p = 0.02). Incidence of lung cancer in the CT group was 645 per 100,000 person-years and 941 per 100,000 person-years in the radiography group (RR 1.13, 95% CI 1.03 – 1.23).

Lung cancer screening with low-dose CT scan in high-risk patients provides a significant mortality benefit. This trial was stopped early because the mortality benefit was so high. The benefit was driven by the reduction in deaths attributed to lung cancer, and when deaths from lung cancer were excluded from the overall mortality analysis, there was no significant difference among the two arms. Largely on the basis of this study, the 2013 USPSTF guidelines for lung cancer screening recommend annual low-dose CT scan in patients who meet NLST inclusion criteria. However, it must be noted that, even in the “ideal” circumstances of this trial performed at experienced centers, 96% of abnormal CT screening results in this trial were actually false positives. Of all positive results, 11% led to invasive studies.

Per UpToDate, since NSLT, there have been several European low-dose CT screening trials published. However, all but one (NELSON) appear to be underpowered to demonstrate a possible mortality reduction. Meta-analysis of all such RCTs could allow for further refinement in risk stratification, frequency of screening, and management of positive screening findings.

No randomized trial has ever demonstrated a mortality benefit of plain chest radiography for lung cancer screening. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial tested this modality vs. “community care,” and because the PLCO trial was ongoing at the time of creation of the NSLT, the NSLT authors trial decided to compare their intervention (CT) to plain chest radiography in case the results of plain chest radiography in PLCO were positive. Ultimately, they were not.

Further Reading:
1. USPSTF Guidelines for Lung Cancer Screening (2013)
2. NLST @ ClinicalTrials.gov
3. NLST @ Wiki Journal Club
4. NLST @ 2 Minute Medicine
5. UpToDate, “Screening for lung cancer”

Summary by Duncan F. Moore, MD

Image Credit: Yale Rosen, CC BY-SA 2.0, via Wikimedia Commons

Week 42 – BeSt

“Clinical and Radiographic Outcomes of Four Different Treatment Strategies in Patients with Early Rheumatoid Arthritis (the BeSt Study).”

Arthritis & Rheumatism. 2005 Nov;52(11):3381-3390. [free full text]

Rheumatoid arthritis (RA) is among the most prevalent of the rheumatic diseases with a lifetime prevalence of 3.6% in women and 1.7% in men [1]. It is a chronic, systemic, inflammatory autoimmune disease of variable clinical course that can severely impact physical functional status and even mortality. Over the past 30 years, as the armamentarium of therapies for RA has exploded, there has been increased debate about the ideal initial therapy. The BeSt (Dutch: Behandel-Strategieën “treatment strategies”) trial was designed to compare, according to the authors, four of “the most frequently used and discussed strategies.” Regimens incorporating traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and newer therapies, such as TNF-alpha inhibitors, were compared directly.

The trial enrolled 508 DMARD-naïve patients with early rheumatoid arthritis. Pertinent exclusion criteria included history of cancer and pre-existing laboratory abnormalities or comorbidities (e.g. elevated creatinine or ALT, alcohol abuse, pregnancy or desire to conceive, etc.) that would preclude the use of various DMARDs. Patients were randomized to one of four treatment groups. Within each regimen, the Disease Activity Score in 44 joints (DAS-44) was assessed q3 months, and, if > 2.4, the medication regimen was uptitrated to the next step within the treatment group.

Four Treatment Groups

  1. Sequential monotherapy: methotrexate (MTX) 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, the following sequence was pursued: sulfasalazine (SSZ) monotherapy, leflunomide monotherapy, MTX + infliximab, gold with methylprednisolone, MTX + cyclosporin A (CSA) + prednisone
  2. Step-up combination therapy: MTX 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, SSZ was added, followed by hydroxychloroquine (HCQ), followed by prednisone. If patients failed to respond to those four drugs, they were switched to MTX + infliximab, then MTX + CSA + prednisone, and finally to leflunomide.
  3. Initial combination therapy with tapered high-dose prednisone: MTX 7.5 mg/week + SSZ 2000 mg/day + prednisone 60mg/day (tapered in 7 weeks to 7.5 mg/day). If insufficient control, MTX was uptitrated to 25-30 mg/week. Next, combination would be switched to MTX + CSA + prednisone, then MTX + infliximab, then leflunomide monotherapy, gold with methylprednisolone, and finally azathioprine with prednisone.
  4. Initial combination therapy with infliximab: MTX 25-30 mg/week + infliximab 3 mg/kg at weeks 0, 2, 6, and q8 weeks thereafter. There was a protocol for infliximab-dose uptitration starting at 3 months. If insufficient control on MTX and infliximab 10 mg/kg, patients were switched to SSZ, then leflunomide, then MTX + CSA + prednisone, then gold + methylprednisolone, and finally AZA with prednisone.

Once clinical response was adequate for at least 6 months, there was a protocol for tapering the drug regimen.

The primary endpoints were: 1) functional ability per the Dutch version of the Health Assessment Questionnaire (D-HAQ), collected by a blinded research nurse q3 months and 2) radiographic joint damage per the modified Sharp/Van der Heijde score (SHS). Pertinent secondary outcomes included DAS-44 score and laboratory evidence of treatment toxicity.

At randomization, enrolled RA patients had a median duration of symptoms of 23 weeks and median duration since diagnosis of RA of 2 weeks. Mean DAS-44 was 4.4 ± 0.9. 72% of patients had erosive disease. Mean D-HAQ score at 3 months was 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (p < 0.001 for groups 1 and 2 vs. groups 3 and 4; paired tests otherwise insignificant). Mean D-HAQ at 1 year was 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (p = 0.010 for group 1 vs. group 3, p = 0.003 for group 1 vs. group 4; paired tests otherwise insignificant). At 1 year, patients in group 3 or 4 had less radiographic progression in joint damage per SHS than patients in group 1 or 2. Median increases in SHS were 2.0, 2.5., 1.0, and 0.5 in groups 1-4, respectively (p = 0.003 for group 1 vs. group 3, p < 0.001 for group 1 versus group 4, p = 0.007 for group 2 vs. group 3, p < 0.001 for group 2 vs. group 4). Regarding DAS-44 score: low disease activity (DAS-44 ≤ 2.4) at 1 year was reached in 53%, 64%, 71%, 74% of groups 1-4, respectively (p = 0.004 for group 1 vs. group 3, p = 0.001 for group 1 vs. group 4, p not significant for other comparisons). There were no group differences in prevalence of adverse effects.

Overall, among patients with early RA, initial combination therapy that included either prednisone (group 3) or infliximab (group 4) resulted in better functional and radiographic improvement than did initial therapy with sequential monotherapy (group 1) or step-up combination therapy (group 2). In the discussion, the authors note that given the treatment group differences in radiographic progression of disease, “starting therapy with a single DMARD would be a missed opportunity in a considerable number of patients.” Contemporary commentary by Weisman notes that “the authors describe both an argument and a counterargument arising from their observations: aggressive treatment with combinations of expensive drugs would ‘overtreat’ a large proportion of patients, yet early suppression of disease activity may have an important influence on subsequent long‐term disability and damage.”

Fourteen years later, it is a bit difficult to place the specific results of this trial in our current practice. Its trial design is absolutely byzantine and compares the 1-year experience of a variety of complex protocols that theoretically have substantial eventual potential overlap. Furthermore, it is difficult to assess if the relatively small group differences in symptom (D-HAQ) and radiographic (SHS) scales were truly clinically significant even if they were statistically significant. The American College of Rheumatology 2015 Guideline for the Treatment of Rheumatoid Arthritis synthesized the immense body of literature that came before and after the BeSt study and ultimately gave a variety of conditional statements about the “best practice” treatment of symptomatic early RA. (See Table 2 on page 8.) The recommendations emphasized DMARD monotherapy as the initial strategy but in the specific setting of a treat-to-target strategy. They also recommended escalation to combination DMARDs or biologics in patients with moderate or high disease activity despite DMARD monotherapy.

References / Additional Reading:
1. “The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases.” Arthritis Rheum. 2011 Mar;63(3):633-9. [https://www.ncbi.nlm.nih.gov/pubmed/21360492]
2. BeSt @ Wiki Journal Club
3. “Progress toward the cure of rheumatoid arthritis? The BeSt study.” Arthritis Rheum. 2005 Nov;52(11):3326-32.
4. “Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis?” Arthritis Rheumatol. 2014 Apr;66(4):775-82. [https://www.ncbi.nlm.nih.gov/pubmed/24757129]
5. “2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis” Arthritis Rheumatol. 2016 Jan;68(1):1-26
6. RheumDAS calculator

Summary by Duncan F. Moore, MD

Image Credit: Braegel, CC BY 3.0, via Wikimedia Commons