Month: September 2019

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]
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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 12 – 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]
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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 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]
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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 10 – EINSTEIN-PE

“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

by the EINSTEIN-PE Investigators

N Engl J Med. 2012 Apr 5;366(14):1287-97. [free full text]
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Prior to the introduction of DOACs, the standard of care for treatment of acute VTE was treatment with a vitamin K antagonist (VKA, e.g. warfarin) bridged with LMWH. In 2010, the EINSTEIN-DVT study demonstrated the non-inferiority of rivaroxaban (Xarelto) versus VKA with an enoxaparin bridge in patients with acute DVT in the prevention of recurrent VTE. Subsequently, in this 2012 study, EINSTEIN-PE, the EINSTEIN investigators examined the potential role for rivaroxaban in the treatment of acute PE.

This open-label RCT compared treatment of acute PE (± DVT) with rivaroxaban (15mg PO BID x21 days, followed by 20mg PO daily) versus VKA with an enoxaparin 1mg/kg BID bridge until the INR was therapeutic for 2+ days and the patient had received at least 5 days of enoxaparin. Patients with cancer were not excluded if they had a life expectancy of ≥ 3 months, but they comprised only ~4.5% of the patient population. Treatment duration was determined by the discretion of the treating physician and was decided prior to randomization. Duration was also a stratifying factor in the randomization. The primary outcome was symptomatic recurrent VTE (fatal or nonfatal). The pre-specified noninferiority margin was 2.0 for the upper limit of the 95% confidence interval of the hazard ratio. The primary safety outcome was “clinically relevant bleeding.”

4833 patients were randomized. In the conventional-therapy group, the INR was in the therapeutic range 62.7% of the time. Symptomatic recurrent VTE occurred in 2.1% of patients in the rivaroxaban group and 1.8% of patients in the conventional-therapy group (HR 1.12, 95% CI 0.75–1.68, p = 0.003 for noninferiority). The p value for superiority of conventional therapy over rivaroxaban was 0.57. A first episode of “clinically relevant bleeding” occurred in 10.3% of the rivaroxaban group versus 11.4% of the conventional-therapy group (HR 0.90, 95% CI 0.76-1.07, p = 0.23).

In a large, open-label RCT, rivaroxaban was shown to be noninferior to standard therapy with a VKA + enoxaparin bridge in the treatment of acute PE. This was the first major RCT to demonstrate the safety and efficacy of a DOAC in the treatment of PE and led to FDA approval of rivaroxaban for the treatment of PE that same year. The following year, the AMPLIFY trial demonstrated that apixaban was noninferior to VKA + LMWH bridge in the prevention of recurrent VTE, and apixaban was also approved by the FDA for the treatment of PE. The 2016 Chest guidelines for Antithrombotic Therapy for VTE Disease recommend the DOACs rivaroxaban, apixaban, dabigatran, or edoxaban over VKA therapy in VTE not associated with cancer. In cancer-associated VTE, LMWH remains the recommended initial agent. (See the Week 1 – CLOT post.) As noted previously, a study in 2018 in NEJM demonstrated the noninferiority of edoxaban over LMWH in the treatment of cancer-associated VTE. Later that year, the SELECT-D trial compared rivaroxaban (Xarelto) to dalteparin and demonstrated a reduced rate of recurrence among patients treated with rivaroxaban (cumulative 6-month event rate of 4% versus 11%, HR 0.43, 95% CI 0.19–0.99) with no difference in rates of major bleeding but increased “clinically relevant nonmajor bleeding” within the rivaroxaban group.

Further Reading/References:
1. EINSTEIN-DVT @ NEJM
2. EINSTEIN-PE @ Wiki Journal Club
3. EINSTEIN-PE @ 2 Minute Medicine
4. AMPLIFY @ Wiki Journal Club
5. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism” NEJM 2018

Summary by Duncan F. Moore, MD

Image Credit: James Heilman, MD / CC BY-SA 4.0 / via WikiMedia Commons