James McCormack, BSc(Pharm), Pharm D, Professor, Faculty of Pharmaceutical Sciences UBC (biography, no disclosures)
What care gaps or frequently asked questions I have noticed
Numerous observational studies have consistently shown in many (but not all) patient populations a correlation between people with higher blood pressure, glucose, and cholesterol numbers, and a greater risk of cardiovascular events such as heart attacks, strokes, and other unwanted outcomes.
However, correlation does not necessarily equal causation, so early on it was not known if a treatment which lowered these numbers would actually reduce a person’s risk of a heart attack or a stroke.
Fortunately, relatively well-designed studies done from the 60s to the 90s fairly consistently showed lowering “big” blood pressures (systolic blood pressures >160mmHg) and using statins (but not so much other drugs that lowered cholesterol) reduced the risk of cardiovascular disease. Interestingly, however when it comes to glucose, prior to 1998 we really had no studies that evaluated the clinical impact of lowering glucose in type-2 diabetics and to-date only one study (UKPDS) has really suggested a specific treatment produces a cardiovascular benefit.
These generally positive results were the basis for the development of catch phrases like “the silent killer”, “cholesterol plugs your arteries” and “know your numbers” becoming a part of mainstream narrative.
So how big was the benefit? Well, in people with no history of cardiovascular disease, the typical result found was as follows. If 100 people were treated for 5 years, 1 to 2 fewer people would end up having a heart attack or stroke. In people with higher baseline risk factors like systolic blood pressures of 180 or so the benefit might be 2-3 percentage points higher. Is an effect of this size important? Well only you and your patients can make that decision for yourself and you need to balance this benefit, with the potential harm, cost, and inconvenience.
These generally positive findings certainly justified to some degree the proliferation of guidelines extolling the importance of fighting a war against these scary numbers. Interestingly, many guidelines went as far as recommending people achieve a specific target blood pressure, cholesterol, and glucose despite the true lack of any well-designed clinical studies supporting these thresholds.
Data that answers these questions or gaps
Over the last 10-15 or so years, researchers with the best of intentions appropriately continued to evaluate the impact newer medications and more aggressive treatment of blood pressure, cholesterol, and glucose had on cardiovascular outcomes.
This led to the publication over the last 6-7 years of at least 18 new and important large well-designed studies. While these studies did not enroll only primary prevention patients they also weren’t exclusively secondary prevention studies. So what did this research show?
Well, first off, every one of them showed the treatments lowered either people’s blood pressure, cholesterol, or glucose numbers.
But what is important is the effect these approaches had on important cardiovascular outcomes and here is where the practice changing moment comes to life.
There were 3 blood pressure studies – ALTITUDE (aliskiren a new drug) and VALISH, ACCORD (which studied more aggressive blood pressure lowering) – and none showed a reduction in important cardiovascular events.
There were 7 cholesterol studies – AIM-HIGH, HPS2-THRIVE (niacin an old drug), ACCORD (fibrate an old drug), dalOUTCOMES (dalcetrapib a new drug) and STABILITY (darapladib a new drug) – did not show a reduction in clinically important outcomes. In the last month 2 studies, OSLER (evolocumab a new drug) with a prespecified but exploratory analysis and ODYSSEY (alirocumab a new drug) with a post-hoc analysis, did report a reduced incidence of cardiovascular events compared to placebo.
There were 8 studies in type 2 diabetes – ACCORD, ADVANCE, VADT (studied more aggressive glucose lowering), ROADMAP (olmesartan a somewhat older drug); ORIGIN (insulin an old drug), SAVOR-TIMI 53 (saxagliptin a new drug), EXAMINE (alogliptin a new drug) and ALECARDIO (aleglitazar a new drug) – and none showed benefit when it came to important patient oriented clinical outcomes and some showed harm.
Appropriately, you may well be saying if this many studies showed little if any important clinical benefit, shouldn’t that make us rethink what are doing? Well, medical beliefs and dogma are often hard to reverse.
What I recommend (practice tip)
Fortunately, in the face of this new information and in addition a re-evaluation of the older studies, a few recent guidelines have started to reflect these findings and change their story a little bit. Blood pressure and glucose guidelines have raised the threshold for treatment in some populations, and some cholesterol guidelines have suggested only statins provide a clinical benefit and cholesterol targets are to some degree being abandoned, which is a least a bit more in line with the best available evidence. In addition, some of them are now promoting the concepts of shared-decision making versus just treating to targets but often don’t provide useful information to help clinicians with this task.
So what does all this mean? First, treating blood pressure, cholesterol and glucose numbers does not necessarily lead to a reduction in important cardiovascular outcomes. This is especially true if the numbers weren’t very high in the first place which is what we see in most people. Before you recommend changing surrogate risk numbers make sure you have a ballpark idea of the baseline risk of bad outcomes that are associated with a patient’s risk factors like age, gender, blood pressure, lipids and glucose and then based on the best available evidence, how big an impact a “proven” treatment may or may not have on that risk.
I have developed a free online CVD risk and benefit calculator that might help some clinicians discuss these issues with their patients. The Absolute CVD Risk/Benefit Calculator (http://cvdcalculator.org) is an interactive and individualized primary prevention cardiovascular risk calculator that provides an absolute estimate (%) of a person’s chance of having a cardiovascular event over a specific period of time and an idea of the potential benefit and harms of treatment (expressed as absolute numbers and NNT/NNH). The calculator includes the top 3 risk databases – Framingham, QRISK2 and ASCVD and the best available evidence from randomized controlled trials to provide the benefit estimates. I would encourage clinicians to use this or at least some type of CVD risk calculator for all primary prevention patients so patients have some idea of the impact of specific risk factors have on their absolute risk of CVD. In addition, they can be given an idea of the magnitude of benefit and potential harms. Armed with this information, clinicians and patients can then really engage in shared-decision making.
Clinical impact of lowering glucose in type-2 diabetics:
- UKPDS, UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352: 854–865. (View with CPSBC or UBC)
3 blood pressure studies – ALTITUDE, VALISH, ACCORD
- ALTITUDE, Parving H, Brenner BM, McMurray JJV, et al. Cardiorenal endpoints in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204. (View)
- VALISH, Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated Systolic hypertension study. Hypertension. 2010;56:196-202. (View with CPSBC or UBC)
- ACCORD -BP, Cushman W, Evans G, Byington R, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1575-1585. (View)
7 cholesterol studies – AIM-HIGH, HPS2-THRIVE, ACCORD, dalOUTCOMES, STABILITY, OSLER and ODYSSEY
- AIM-HIGH, Boden W, Probstfield J, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267. (View)
- HPS2-THRIVE, The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-212. (View)
- ACCORD- LIPID, Ginsberg H, Elam M, Lovato L, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574. (View)
- dal-OUTCOMES, Schwartz G, Olsson A, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-2099. (View)
- STABILITY, White H, Held C, Stewart R, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702-1711. (View)
- OSLER, Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of Evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015:150315080057008. (Request from CPSBC or view with UBC)
- ODYSSEY, Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015:150320053923003. (Request from CPSBC or view with UBC)
8 studies in type 2 diabetes – ACCORD, ADVANCE, VADT, ROADMAP, ORIGIN, SAVOR-TIMI 53, EXAMINE, and ALECARDIO
- ACCORD, Gerstein H, Miller M, Byington R, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-2559. (View)
- ADVANCE, Joshi R, Grobbee D, Cooper M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. (View)
- VADT, Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139. (View)
- ROADMAP, Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907-917. (View)
- ORIGIN, Gerstein H, Bosch J, Dagenais G, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-328. (View)
- SAVOR-TIMI 53, Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. (View)
- EXAMINE, White WB, Cannon CP, Heller SR, et al.; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35. (View)
- ALECARDIO, Schwartz GG, Cannata R, Malmberg K, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the alecardio randomized clinical trial. JAMA. 2014;311:1515-1525. (Request from CPSBC or view with UBC)
Absolute CVD Risk/Benefit Calculator (http://cvdcalculator.org)
BC Guidelines http://www.bcguidelines.ca:
- Cardiovascular Disease – Primary Prevention (2014)
- Hypertension (2008), new version 2015
- Diabetes Care (2010), new version Dec 2015
3 risk calculators – Framingham, QRISK2 and ASCVD
- Framingham, Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. The Lancet. 2009;373:739-745. (View with CPSBC or UBC)
- QRISK2, Christiaens, Hippisley-Cox J, Coupland C, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ. 2008;336:1475-1482. (View)
- ACC/AHA ASCVD (Pooled Cohort Risk Assessment Equations), Stone N, Robinson J, Lichtenstein A, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;63:2889-2934. (View with CPSBC or UBC)