Fact: I did not appreciate how important clinical trials would become in my every day life as an APPE student when I first took a biostatistics class during P1 year. Our ability to analyze and evaluate data from clinical trials is critical to providing evidence-based recommendations to our healthcare team. Although guidelines are also a great source of information, your preceptors will soon expect you know the landmark trials that set the foundation for the guidelines. When I first got out onto rotation I had no idea where to look for these landmark trials, so I asked, I googled, and I compiled. Now I have a pretty hefty dropbox filled with landmark trials relevant to each rotation I've been on! Since I'm currently on primary care, I figured I'd list some of the landmark trials we talk about the most and use the most in our every day practice.

Disclaimer: this is by no means totally comprehensive. I am very aware there are more trials than just these. These were picked at random and also listed at random. Also, I've tried not to enter in my own opinion because if I did I'd probably have a novel on my hands here.

1. SPRINT (2015)
Investigated if intensive BP control (target SBP <120 mmHg) in patients at high risk for CVD (without a history of stroke or diabetes) yielded CV outcomes superior to standard BP control (135-139 mmHg)

Primary end point: composite outcome of MI, ACS without MI, stroke, CV death and acute HF

Outcome: the trial was stopped after 3 years after an interim analysis showed superiority of intensive BP control compared to standard BP control. For the primary end point: 5.2% vs. 6.8%; P<0.001; NNT 63. There were more ADE (hypotension, syncope and AKI) observed in the intensive BP control arm.

2. ACCORD (2008) AND ACCORD-BP (2010)
Accord
Investigated whether intensive HbA1c goals (<6%) in patients with T2DM and baseline HbA1c >7.5% reduces the risk of CV events compared to standard HbA1c goals (7-7.9%)

Primary end point: annual rate of nonfatal MI or nonfatal stroke or CV death

Outcome: There was no difference in the primary end point between the two arms (2.11% vs. 2.29%; HR 0.90; 95% CI 0.78-1.04; P=0.16). The trial was stopped early (after 3.7 yrs) due to the observed increase in all cause mortality (NNH=370) and CV mortality. Now we only recommend intensive HbA1c lowering in certain populations.

Accord-BP
Does intensive BP control (SBP <120 mmHg) reduce the rates CV events when compared to the standard BP control (SBP <140 mmHg) in patients with T2DM and at high risk for CV events.

Primary end point: annual rate of nonfatal MI, nonfatal stroke or CV death

Outcome: There was no difference between the two study arms (1.87% vs. 2.09%; HR 0.88; 95% CI 0.73-1.06; P=0.20). JNC8 subsequently used this to determine their goal for diabetics (<140/90 mmHg). The intensive BP control arm did experience more side effects and were on more HTN medications compared to standard control (NNH 49).

3. IMPROVE-IT (2015)
Investigated whether the combination of ezetimibe and simvastatin reduces a composite CV outcome in patients with recent ACS compared to simvastatin monotherapy.

Primary end point: composite end point of CV mortality, nonfatal stroke or major CV event

Outcome: The combination of ezetimibe and simvastatin significantly reduced the rate of the composite primary end point (34.7% vs. 32.7%; P=0.016; NNT 50), but was most likely led by reductions seen in MI and stroke. The addition of ezetimibe to simvastatin provides about a 23-25% reduction in LDL-C. This trial hasn't changed practice very much, also worth noting the AAR was 2%.

4. UKPDS 34 (1998)
Investigated whether metformin reduces DM-related complications and all cause mortality when compared to other intensive agents and diet changes in newly diagnosed T2DM patients who are also overweight.

3 arms included metformin vs. diet vs. intensive treatment (chlorpropamide, glibenclamide or insulin)

Primary end point: all cause mortality, DM-specific mortality and DM-specific end points

Outcome: Metformin was associated with a reduction in all cause mortality DM related complications when compared to the other two arms but metformin vs. diet was the primary analysis. This trial is why we use metformin first line for newly diagnosed T2DM patients.

5. ACCOMPLISH (2008)
This trial compared the ability of benazepril/amlodipine vs. benazepril/HCTZ to reduce CV events in hypertensive patients at risk for CV complications.

Primary end point: composite of CV mortality, nonfatal MI, nonfatal CVA, UA, coronary revascularization or resuscitation after cardiac arrest

Outcome: Benazepril/amlodipine was associated with a reduction in the composite primary end point (9.6% vs. 11.8%; HR 0.80; 95% CI 0.72-0.90; P<0.001). Consider that they used HCTZ vs. Chlorthalidone for their diuretic (HCTZ is shorter acting and may be worse when it comes to 24 hour BP control).

6. SMART (2006)
Investigated whether use of a long-acting beta2 agonist (LABAs) in asthmatics increases mortality and other respiratory related ADE.

Primary end point: respiratory-related death or life-threatening events

Outcome: there was no difference found between the two arms for the primary composite end point. Importantly, there were increases observed in the following secondary outcomes: asthma-related deaths or life-threatening events, death from asthma and respiratory related death. These outcomes were more pronounced in subgroup analyses for African Americans and those not using corticosteroid inhalers. Because of this trial, LABAs are added to ICS in step 3 of asthma treatment, and they have a black box warning for asthma-related death.


7. EMPA-REG OUTCOME (2015)
Compared empagliflozin 10mg and 25mg to placebo in reducing composite end point CV event outcome in patients with T2DM at risk for CV events.

Primary end point: composite CV mortality, nonfatal MI or nonfatal stroke

Outcome: Reduction in the primary end point was observed with empagliflozin (10.5% vs. 12.1%; P=0.04). There was also an observed reduction in all-cause mortality and CV mortality. A1c reduction with empagliflozin was about 0.5%. Worth noting that the empagliflozin dose groups were pooled in the analysis.


8. LEADER (2016)
Investigated whether liraglutide reduced composite CV end point in T2DM patients at risk for CV events compared to placebo

Primary end point: composite of first occurrence of CV mortality, nonfatal stroke, or nonfatal MI

Outcomes: liraglutide achieved reduction in the primary end point (13.0% vs. 14.9%; HR 0.87; 95% CI 0.78 -0.97; P<0.001) and also showed statistical significance in the all-cause mortality analysis. Unfortunately, only modest reductions in HbA1c were observed and no one achieved an A1c <7%.

9. HOPE (2000) AND MICRO-HOPE
Hope
Investigated whether Ramipril reduces the rate of CV events with patients who have multiple CV risk factors but not heart failure.

Primary end point: composite of MI, stroke, and CV death

Outcomes: Ramipril signficantly lowered the rate of the composite primary end point (14.0% vs. 17.8%; HR 0.78; 95% CI 0.70-0.86; P<0.001; NNT 27). Benefits were seen in all sub group analyses, and there was a statistically significant reduction observed in all-cause mortality.

The MICRO-HOPE substudy investigated the effects of Ramipril on microvascular complications in T2DM such as microalbuminuria and nephropathy. Ramipril was found to also prevent overt nephropathy and have renoprotective effects.

10. HEART PROTECTION STUDY (2002)
Investigated whether simvastatin would reduce CV mortality and morbidity in those at high risk for CVD

Primary end point: All cause mortality, CV mortality, coronary mortality, vascular and non-vascular mortality

Outcomes: The reduction in all cause mortality caused by the simvastatin group was statistically significant (P=0.0003) vs. placebo, and there were benefits seen in coronary and vascular mortality. Essentially there was no LDL-C threshold where they didn't see a benefit, and effect did not differ based on baseline cholesterol.

11. CANVAS (2017)
Studied whether canagliflozin lowered the risk of CV events compared to placebo in patients with T2DM at high risk for developing CV events?

Primary end point: composite of CV mortality, nonfatal MI, nonfatal stroke

Outcomes: canagliflozin significantly reduced the rate of CV death and nonfatal CV events. There were also benefits seen in renal protection. Investigators saw a similar rate of reduction in HbA1c compared to empagliflozin (0.5%) but weirdly enough, canagliflozin was associated with an increased risk of amputation in this study.


12. TORCH (2007)
Investigated the ability of salmaterol/fluticasone combination therapy to reduce mortality in patients with COPD

Primary end point: All-cause mortality at 3 years and COPD-related mortality at 3 years

Outcomes: combination therapy slowed lung function decline, improved quality of life, and reduced exacerbations and hospitalizations. However the combo arm did not achieve statistical significance with the primary end point, despite there being a trend in reduction (P=0.052).

13. WISDOM (2014)
This study investigated whether you could safely taper inhaled corticosteroids off in severe COPD patients with stable symptoms who were on triple therapy (tiotropium, fluticasone and salmaterol).

Primary end point: time to first COPD exacerbation in the first 12mo after ICS withdrawal

Outcomes: ICS withdrawal does not increase the risk of COPD exacerbation and is generally safe. Basically this trial concluded that we have to weigh the risk with each patient. We don't know the long term benefits of withdrawing ICS but we do know they increase the risk for pneumonia, and they may also slow FEV1 decline. So assess on a patient-by-patient basis.

14. ALLHAT (2002)
This trial compared chlorthalidone, lisinopril and amlodpine in reducing CV events in patients with HTN

Primary end point: Fatal CAD or nonfatal MI at 6 years

Outcomes: Chlorthalidone emerged from underdog to super star. Compared to amlodipine it reduced the incidence of CHF, and compared to lisinopril it decreased the incidence of CAD, stroke, CHF and angina. Essentially this is where JNC8 got their first line agents. Alpha-antagonist doxazosin was dropped from this when they found it increased CHF compared to chlorthalidone.

15. JUPITER (2008)
Investigated whether rosuvastatin decreased the rate of CV events in patients with normal LDL-C and elevated CRP.

Primary end point: First major CV event (its a composite of a lot of CV outcomes)

Outcomes: Rosuvastatin reduced LDL-C, CRP and also the incidence of major CV events. However, the trial is widely criticized for being stopped early.