We are pleased to have treated over 3,000 patients in 2021 with our differentiated portfolio of TMTT therapies, gaining valuable learnings through both our clinical and commercial experiences.
Underlying sales increased 18% to $5.2 billion, driven by balanced organic sales growth in each region.
We achieved 19% growth in adjusted earnings per share, while also increasing R&D, 19%.
Fourth quarter sales of $1.3 billion increased 13% on a constant currency basis versus the year ago period.
Growth was driven by our portfolio of innovative technologies, although at the lower end of our October expectations due to the pronounced impact of Omicron on hospital resources in December, especially in the U.S. Full year 2021 global TAVR sales of $3.4 billion increased 18% on an underlying basis versus the prior year.
Despite intermittent challenges associated with the pandemic throughout the year, sales were in line with our original guidance of 3.2 to 3.6 billion and were driven by increased awareness of the benefits of TAVR therapy with our SAPIEN platform.
In the fourth quarter, our global TAVR sales were $872 million, an increase of 13% on an underlying basis, with impressive strength outside the U.S.
In the U.S., our TAVR sales grew 10% year over year in the fourth quarter, and we estimate that our share of procedures was stable.
Outside the U.S., in the fourth quarter, our sales grew approximately 20% year over year on an underlying basis, and we estimate total TAVR procedure growth was comparable.
It's worth noting that a recent cost-effectiveness study demonstrated that TAVR with SAPIEN 3 was economically dominant when compared to surgical aortic valve replacement in treating French patients with severe symptomatic aortic stenosis who are at low surgical mortality -- who are at low risk of surgical mortality.
We're also encouraged by the recently published guidelines from the European Association of Cardiothoracic Surgery, which now definitively recommend TAVR for patients over 75.
Additionally, in Q4, we received FDA approval to use SAPIEN 3 with our Alterra adaptive pre-stent for congenital heart patients.
In summary, despite a slower-than-expected start to the year, we continue to anticipate 2022 underlying TAVR sales growth of 12 to 15%, consistent with the range we shared at our December investor conference.
We remain confident in this large global opportunity will double to $10 billion by 2028, which implies a compounded annual growth rate in the low double-digit range.
At the PCR London Valves conference in Q4, PASCAL 30-day outcomes from our MiCLASP post-market approval study of more than 250 patients in Europe were presented.
Fourth quarter revenue of $25 million grew sequentially from the third quarter as we saw increased adoption of the PASCAL system despite the negative COVID impact in December.
Full year 2021 global sales more than doubled to $86 million.
Despite the COVID impact so far this year, we continue to expect TMTT sales of 140 to $170 million for 2022.
We estimate the global TMTT opportunity will grow to approximately $5 billion by 2028, and we remain committed to bringing our groundbreaking portfolio of therapies to patients with these life-threatening diseases.
In Surgical Structural Heart, full year global sales were $889 million, up 15% on an underlying basis versus the prior year.
Fourth quarter 2021 global sales of $221 million increased 9% on an underlying basis over the prior year.
Full year global sales of $835 million increased 14% on an underlying basis versus the prior year.
2021 growth was driven by balanced contributions from all product lines led by HemoSphere sales as capital spending resumed.
Fourth quarter Critical Care sales of $212 million increased 8% on an underlying basis, driven by strong demand for HemoSphere.
Sales in the fourth quarter increased 12.6% on an underlying basis.
Adjusted earnings per share was $0.51, and GAAP earnings per share was $0.53.
Our fourth quarter sales were negatively impacted by the wave of COVID that began late in the quarter, especially in the U.S. Earnings per share in the quarter was below our expectations as it was impacted by weaker-than-expected sales and we accelerated certain spending into the fourth quarter of 2021 that we had planned to incur during 2022, including preparation for TMTT product launches.
For the full year 2021, we are pleased with our performance as sales increased 18% on an underlying basis to $5.2 billion and adjusted earnings per share grew 19% to $2.22.
For the fourth quarter, our adjusted gross profit margin was 76.8%, compared to 75.3% in the same period last year.
We continue to expect our full year 2022 adjusted gross profit margin to be between 78 and 79%.
Selling, general and administrative expenses in the fourth quarter were $424 million or 31.9% of sales, compared to $339 million in the prior year.
We continue to expect full year 2022 SG&A as a percent of sales, excluding special items, to be between 28 and 30%.
Research and development expenses in the quarter grew 19% to $233 million or 17.5% of sales.
For the full year 2022, we continue to expect R&D as a percentage of sales to be in the 17 to 18% range as we invest in developing new technologies and generating evidence to support TAVR and TMTT growth.
During the fourth quarter, we recorded an $18 million net reduction in the fair value of our contingent consideration liabilities, which benefited earnings per share by $0.03.
This gain was excluded from the adjusted earnings per share of $0.51 I mentioned earlier.
Our reported tax rate this quarter was 10.9% or 12.7%, excluding the impact of special items.
This rate included an approximate 3 percentage point benefit from the accounting for stock-based compensation.
Our full year 2021 tax rate, excluding special items, was 12.6%.
We continue to expect our full year rate in 2022 to be between 11 and 15%, which includes an estimated benefit of 3 percentage points from stock-based compensation accounting.
Foreign exchange rates decreased fourth quarter reported sales by approximately 1% or $10 million compared to the prior year.
At current rates, we now expect an approximate $100 million negative impact or about 2% to full year 2022 sales as compared to 2021.
Foreign exchange rates positively impacted our fourth quarter gross profit margin by 140 basis points compared to the prior year.
Free cash flow for the fourth quarter was $284 million, defined as cash flow from operating activities of $374 million, less capital spending of $90 million.
Full year 2021 free cash flow was $1.4 billion, up from $734 million in 2020.
We continue to expect full year 2022 free cash flow to be between 1.2 and $1.5 billion.
In 2022, we expect our cash flow will be reduced by approximately $200 million due to a change in tax regulations involving the timing of the deductions for research and development expenses.
We have a strong balance sheet, with approximately $1.5 billion in cash, cash equivalents, and short-term investments at the end of the year.
Consistent with our practice of opportunistically repurchasing shares, we purchased approximately $100 million during the fourth quarter.
We still have remaining share repurchase authorization of $1.1 billion.
Average shares outstanding during the fourth quarter were $632 million, relatively consistent with the prior quarter.
We continue to expect average diluted shares outstanding for 2022 to be between 630 and $635 million.
For total Edwards, we continue to expect sales to grow at a low double-digit rate to 5.5 billion to $6 billion.
For TAVR, we expect sales of 3.7 to $4 billion.
And for TMTT, we expect sales of 140 to $170 million.
We expect Surgical Structural Heart sales of 870 to $950 million and Critical Care sales of 820 to $900 million.
For full year 2022, we continue to expect adjusted earnings per share of $2.50 to $2.65.
For the first quarter of 2022, we project total sales to be between 1.27 and $1.35 billion and adjusted earnings per share of $0.54 to $0.62.
1 largest health burden, we believe the opportunity to serve our patients will nearly double between now and 2028.

Summary:
Fourth quarter sales of $1.3 billion increased 13% on a constant currency basis versus the year ago period.
In the fourth quarter, our global TAVR sales were $872 million, an increase of 13% on an underlying basis, with impressive strength outside the U.S.
2021 growth was driven by balanced contributions from all product lines led by HemoSphere sales as capital spending resumed.
Adjusted earnings per share was $0.51, and GAAP earnings per share was $0.53.
Our fourth quarter sales were negatively impacted by the wave of COVID that began late in the quarter, especially in the U.S. Earnings per share in the quarter was below our expectations as it was impacted by weaker-than-expected sales and we accelerated certain spending into the fourth quarter of 2021 that we had planned to incur during 2022, including preparation for TMTT product launches.
We still have remaining share repurchase authorization of $1.1 billion.
For the first quarter of 2022, we project total sales to be between 1.27 and $1.35 billion and adjusted earnings per share of $0.54 to $0.62.
1 largest health burden, we believe the opportunity to serve our patients will nearly double between now and 2028.